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Abstract

Background:

Point-of-care (POC) strip-based blood glucose monitoring systems (BGMSs) used by health care professionals must be more robust than those used for patient self-testing, due to a higher likelihood of BG interferents present in the blood of hospitalized patients. The Cobas® Pulse system (Roche Diagnostics GmbH, Mannheim, Germany) is a novel strip-based POC BGMS designed for multiple patient use in professional health care environments. We report a series of experiments evaluating the effects of several potential interferents, and of extreme conditions, on the BGMS’s performance.

Methods:

Blood samples were spiked with glucose and various potential interferents or tested at extreme environmental conditions. Studies were performed using three lots of Cobas glucose test strips (Roche Diagnostics GmbH, Mannheim, Germany). Interference results over all test strip lots are expressed as the absolute or relative mean bias between test and control.

Results:

Compared with control, the mean absolute or relative bias did not exceed ±10 mg/dL or ±10% for any endogenous substance or drug tested, any combination of hematocrit level or glucose concentration over the ranges tested, or any test at altitudes up to 4300 m above sea level, with any of the three test strip lots. Varying oxygen concentrations (partial pressure) in a blood sample did not affect glucose measurements. All interference results were within the specified accuracy limits. Contamination of blood samples with skin disinfectants, extreme levels of ascorbic acid, or hematocrit levels outside the claimed range did not cause wrong test results.

Conclusions:

POC BGMS performance was not altered by interfering substances after a rigorous evaluation under a wide range of conditions.

Keywords

blood glucose monitoring systems extreme conditions hospitalized patients interference factors

Introduction

Point-of-care (POC) strip-based blood glucose (BG) meters are widely used by patients for self-monitoring of BG and by health care professionals for assessment of BG levels in health care settings. BG monitoring systems (BGMSs) used by health care professionals must be more robust than those used for patient self-testing. Hospitalized patients have inherently more complex medical issues than outpatients and are likely to be receiving multiple medications or have wide variations in laboratory parameters, both of which have the potential to interfere with BG measurements.^1-4 This is particularly true in critically ill patients, where stress-induced hyperglycemia is common even without a prior diabetes mellitus diagnosis.⁵ Hyperglycemia has been associated with longer hospital stays, increased complication rates, and higher mortality.^6,7 Hence, control of hyperglycemia through frequent BG monitoring is vital in critically ill patients. Control of hyperglycemia is often achieved through treatment with insulin, which requires frequent BG monitoring for safe and effective use.

Biochemical, chemical, and electrochemical side reactions resulting from extreme variations in the properties of blood or the presence of electroactive substances, have the potential to interfere with the detection principle of BGMSs.^8,9 Thus, potential interference from endogenous substances, drugs, and variations in hematocrit levels and environmental conditions must be thoroughly evaluated in the development of any novel strip-based BGMS. To facilitate this process, the U.S. Food and Drug Administration (FDA) has issued a guidance document for industry and FDA staff¹⁰ that includes recommendations for evaluating the potential for interference with BGMSs intended for use in professional health care settings.

The Cobas® Pulse system (Roche Diagnostics GmbH, Mannheim, Germany) is a novel strip-based POC BGMS designed specifically for multiple patient use in professional health care environments.¹¹ A multicenter evaluation using samples from patients in diverse clinical settings by intended POC test operators showed that the BGMS is effective for measuring BG in venous, arterial, neonatal arterial, neonatal heel stick, and capillary whole blood samples, and that it is a valid alternative to other currently approved testing methods.¹²

The BGMS has been designed with multiple failsafes to improve accuracy and significantly reduce the risk of incorrect test results caused by user error.

In principle, three basic interference mechanisms can potentially lead to problematic deviations in BG concentration measurements in a BGMS with enzymatic and electrochemical components. First, nonspecific reactions between the enzyme system and nonglucose sugars in a blood sample can cause false-positive bias. Second, the physical characteristics of the blood sample, including variation in hematocrit levels, lipid, protein, or electrolyte levels, and temperature can have a direct effect on the voltammetric measuring principle. Third, certain endogenous or exogenous substances (e.g., drugs) can electrochemically or chemically react with components of the detection chemistry and cause biased BG concentration measurements (mostly high and low bias). Moreover, the use of a dehydrogenase, rather than an oxidase enzyme, eliminates the influence of oxygen concentration in a blood sample. Variations in the physical components of blood are compensated for by incorporating a poly-frequent impedimetric measuring method in addition to the voltammetric measuring method, simultaneous application of both methods in the test sequence, and by the algorithm that calculates the glucose concentration. To compensate for endogenous or exogenous substances, which can produce background currents, both electrodes in the test strip are coated with the same reagent, but only one electrode contains the glucose-specific enzyme. Polarization is carried out in both directions during the test sequence and by appropriately calculating the measurement data, response currents that are not correlated to the glucose concentration can be canceled out.

A key goal during the development of the BGMS was demonstrating the absence of clinically relevant interference with BG measurements.¹¹ Here we report the results of a series of experiments designed to evaluate the effects of endogenous substances, frequently used therapeutic drugs, and variation in hematocrit levels, oxygen partial pressure, and altitude on the performance of the BGMS. We also report a series of experiments (“flex studies”) designed to evaluate the effects of extremes of conditions (use of skin disinfectants, high ascorbic acid concentrations, hematocrit levels outside of claimed ranges) to assess risk mitigation in the context of BGMS risks or use by untrained operators.

Methods

This analytical study was performed at Roche in Mannheim, Germany. As such, Ethics Committee approval was only necessary for studies to which § 24 Nr. 1–3 German Medical Device Act (“MPG”) apply (i.e., invasive sampling is conducted either exclusively or to a considerably higher degree to obtain a specimen for the purpose of a performance evaluation of an in vitro diagnostic medical device; in the context of the performance evaluation study, additional invasive or other stressful examinations are conducted; or the results obtained in the context of the performance evaluation are to be used for diagnostic purposes without it being possible to confirm them by means of established procedures). In the remaining cases, the consent of the person from whom the specimen was to be taken was necessary, insofar as this person’s personal rights or commercial interests were affected. The Ethics Committees in Germany decline to review clinical studies using samples that do not fall under the conditions described above, unless they are performed by a medical doctor. In case of involvement of a medical doctor, the Ethics Committee review and counsel the doctor.

The blood samples used in this study were collected from healthy Roche employees in Germany under informed consent via the Roche Medical Services. Samples were collected in anticoagulant tubes and stored overnight at room temperature for glycolyzing. They were then spiked with glucose (to adjust for different glucose levels) and the various interference substances according to internal test protocols. Depending on the experiment, the hematocrit level of the samples was also altered.

Studies of endogenous substances and drugs were performed according to the stipulations of the Clinical and Laboratory Standards Institute (CLSI) EP07-A3¹³ and CLSI EP37-A1.¹⁴

Studies of endogenous substances, hematocrit level, oxygen partial pressure, and altitude, and the flex studies, were conducted with spiked venous lithium heparin whole blood. Lithium heparin whole blood was also used to test potentially interfering drugs if the drug was dissolved in an inorganic solvent. Studies with drugs were conducted with spiked lithium heparin plasma if the drug was not sufficiently soluble in aqueous media and had to be dissolved in an organic solvent. In the case of mannitol, the drug was dissolved directly in lithium heparin whole blood.

Both endogenous substances and drugs were tested across three glucose concentration ranges (50-70, 110-130, and 225-270 mg/dL).

Performance was evaluated at four partial pressures of oxygen (30, 60, 90, and 200 mm Hg) that were confirmed on a Cobas b 221 system (blood gas and electrolyte analyzer, Roche Diagnostics GmbH, Mannheim, Germany) and across three glucose concentration ranges (50-70, 110-130, and 225-270 mg/dL).

Studies of hematocrit levels were conducted with 13 hematocrit values (5%, 10%, 15%, 20%, 25%, 30%, 35%, 50%, 55%, 60%, 65%, 70%, and at a nominal value of 42%) across five glucose concentration ranges (30-50, 51-110, 111-150, 151-250, and 251-400 mg/dL).

Studies of altitude were conducted in Mannheim, Germany at an altitude of approximately 90 m above sea level (control) and in a helicopter at altitudes up to approximately 4300 m above sea level across three glucose concentration ranges (50-65, 100-120, and 200-250 mg/dL). The crew was provided with oxygen as a safety measure. After the height was achieved, the sample container was opened, resealed, and inverted to allow the blood sample to adjust to atmospheric oxygen pressure before testing.

All studies were performed using three lots of Cobas glucose test strips (Roche Diagnostics GmbH, Mannheim, Germany). In evaluations of endogenous substances, drugs, and hematocrit levels, each test strip lot was tested with 10 replicates per glucose concentration and condition. In evaluations of oxygen partial pressure, each strip lot was tested with 16 replicates per glucose concentration and condition. In evaluations of altitude, each strip lot was tested with eight replicates per glucose concentration and condition.

Endogenous Substances and Drugs

Each potential interfering endogenous substance (or drug) was measured against a control condition in blood or plasma containing the same solvent as the test condition. Where possible, the concentrations tested were derived from CLSI EP7/EP37 or FDA guidance,^10,13,14 or published literature; for details please refer to the lists of potential interferents (Supplementary Tables S1 and S2).

Hematocrit Levels

The results for hematocrit levels were compared to BG results obtained with a comparator method (plasma-based hexokinase [HK] method on Cobas 6000 Analyzer Series, Roche Diagnostics GmbH, Mannheim, Germany) and to the mean value for the nominal hematocrit value of 42%.

Oxygen

The results for oxygen partial pressure were compared to BG results obtained with the comparator method used for hematocrit, above.

Statistical Methods

Results over all test strip lots are expressed as the absolute or relative mean bias between test and control. Upper and lower 95% confidence intervals were calculated for informational purposes only.

Acceptance Criteria

Acceptance criteria for endogenous substances and drugs were x ±10.0 mg/dL for glucose concentrations <75 mg/dL, where x is the mean absolute bias between test and control value, and x ±10.0% for glucose concentrations ≥75 mg/dL, where x is the mean relative bias between test and control value.

Acceptance criteria for hematocrit levels were x ±10.0 mg/dL for glucose concentrations <75 mg/dL, where x is the mean absolute bias between test and reference value, and x ±10.0% for glucose concentrations ≥75 mg/dL, where x is the mean relative bias between test and reference value. Note that the bias is not only between the test and reference value, but also between the test and mean value for the nominal hematocrit value of 42%.

Acceptance criteria for altitude were x ±10.0 mg/dL for glucose concentrations <100 mg/dL, where x is the mean absolute bias between test and control condition, and x ±10.0% for glucose concentrations ≥100 mg/dL, where x is the mean relative bias between test and control condition.

Acceptance criteria for oxygen partial pressure required that 95% of results fall within ±12 mg/dL (for glucose concentrations <75 mg/dL) and ±12% (for glucose concentrations ≥75 mg/dL) of the reference value, and that 98% of glucose results for within ±15 mg/dL (for glucose concentrations <75 mg/dL) and ±15% (for glucose concentrations ≥75 mg/dL) of the reference value.

Flex Studies

Methodologies for flex studies are shown in the Supplementary Information.

Data and Resource Availability

This study was conducted in accordance with applicable regulations. There may be ethical, legal, or other restrictions on sharing the de-identified dataset used for our analysis. Please send any data requests to datasharingrequests@roche.com.

Results

Endogenous Substances

When compared with control, the mean absolute or relative bias did not exceed ±10 mg/dL or ±10% for any endogenous substance tested with any of the three strip lots. Pooled results for 30 replicates (10 for each of three strip lots tested) are presented in Table 1.

Table 1.

Potential Interference by Endogenous Substances Pooled Over Three Test Strip Lots.

Endogenous substance, concentration (mg/dL unless stated differently)	BG concentration
	Control sample (mg/dL)	Control sample, mean (mg/dL)	Test sample, mean (mg/dL)	Test sample (N)	Absolute bias (mg/dL)	Relative bias (%)	Lower CI for absolute bias (mg/dL)	Upper CI for absolute bias (mg/dL)	Lower CI for relative bias (%)	Upper CI for relative bias (%)
Acetoacetate, 20	59.8	57.5	56.9	30	−0.633	−1.10	−1.28	0.0111	−2.22	0.0193
	127.6	124	124	30	−0.633	−0.509	−1.30	0.0349	−1.05	0.0281
	261.3	256	255	30	−1.03	−0.404	−2.06	−0.0109	−0.804	−0.0043
Acetone, 100	59.8	57.5	56.8	30	−0.733	−1.27	−1.29	−0.181	−2.23	−0.314
	127.6	124	123	30	−1.10	−0.884	−1.72	−0.475	−1.39	−0.382
	261.3	256	254	30	−2.07	−0.808	−3.18	−0.949	−1.25	−0.371
Albumin, human, 6000	62.6	63.4	60.7	30	−2.73	−4.31	−3.37	−2.10	−5.31	−3.31
	126.9	129	125	30	−3.67.	−2.84	−4.43	−2.91	−3.43	−2.25
	258.4	260	253	30	−6.80	−2.61	−7.85	−5.75	−3.02	−2.21
ß-Hydroxybutyrate, Na, 265	59.3	59	58.1	30	−0.833	−1.41	−1.32	−0.351	−2.23	−0.596
	122.4	121	121	30	−0.433	−0.357	−1.18	0.311	−0.970	0.256
	259.5	261	261	30	−0.133	−0.0511	−1.18	0.912	−0.451	0.349
Bilirubin, conjugated, 50	58.9	58.4	56.7	30	−1.70	−2.91	−2.28	−1.12	−3.90	−1.92
	126.0	122	122	30	−0.333	−0.272	−1.15	0.481	−0.938	0.393
	251.6	254	248	30	−5.23	−2.06	−6.33	−4.13	−2.50	−1.63
Bilirubin, unconjugated, 40	55.5	55.9	53.2	30	−2.67	−4.77	−3.15	−2.19	−5.63	−3.91
	115	116	116	30	−0.600	−0.515	−1.28	0.0786	−1.10	0.0676
	255.6	253	254	30	0.633	0.250	−0.695	1.96	−0.274	0.775
Biotin, 3	60.8	62.6	60.8	30	−1.80	−2.88	−2.34	−1.26	−3.74	−2.02
	124.5	129	128	30	−0.767	−0.593	−1.57	0.0368	−1.22	0.0285
	257.3	264	266	30	2.40	0.910	1.31	3.49	0.497	1.32
Calcium (chloride), 20	59.8	57.5	58.1	30	0.533	0.927	−0.122	1.19	−0.213	2.07
	127.6	124	124	30	−0.100	−0.0803	−0.820	0.620	−0.659	0.498
	261.3	256	255	30	−1.10	−0.430	−2.09	−0.113	−0.816	−0.0442
Cholesterol, 500	62.6	63.4	56.4	30	−7.03	−11.1	−7.70	−6.37	−12.1	−10.0
	126.9	129	118	30	−11.4	−8.84	−12.1	−10.7	−9.42	−8.27
	258.4	260	238	30	−22.0	−8.44	−23.2	−20.7	−8.91	−7.97
Citric acid, 384.3	60.6	59.8	60.3	30	0.467	0.780	−0.103	1.04	−0.172	1.73
	118.9	117	116	30	−1.20	−1.02	−1.99	−0.410	−1.70	−0.350
	251.1	247	237	30	−10.0	−4.06	−11.4	−8.70	−4.60	−3.52
Creatinine, 15	59.2	56.9	56.3	30	−0.600	−1.05	−1.07	−0.127	−1.88	−0.223
	127.0	123	121	30	−2.27	−1.84	−2.91	−1.62	−2.37	−1.32
	259.8	253	246	30	−6.93	−2.74	−8.08	−5.79	−3.19	−2.28
Fructose, 18	60.6	59.8	59.5	30	−0.333	−0.557	−0.792	0.125	−1.32	0.209
	118.9	117	117	30	0.367	0.313	−0.425	1.16	−0.363	0.989
	251.1	247	248	30	0.733	0.297	−0.523	1.99	−0.212	0.805
Galactose, 60	59.2	56.9	55.5	30	−1.40	−2.46	−1.90	−0.904	−3.33	−1.59
	127.0	123	123	30	−0.600	−0.487	−1.25	0.0493	−1.01	0.040
	259.8	253	253	30	−0.567	−0.224	−1.70	0.564	−0.670	0.223
Galactose-1-phosphate, 500	59.6	58.4	57.5	30	−0.867	−1.48	−1.33	−0.403	−2.28	−0.690
	120.9	119	117	30	−1.57	−1.32	−2.19	−0.945	−1.84	−0.796
	248.8	243	243	30	−0.0333	−0.0137	−1.21	1.14	−0.498	0.470
Glutathione, reduced, 5	65.8	64.8	66.6	30	1.80	2.78	1.19	2.41	1.83	3.72
	129.1	127	126	30	−1.13	−0.893	−1.99	−0.277	−1.57	−0.218
	263.1	262	254	30	−8.00	−3.06	−9.05	−6.95	−3.46	−2.66
Glycerol, 17	60.6	59.8	59.2	30	−0.600	−1.00	−1.11	−0.0943	−1.85	−0.158
	118.9	117	117	30	−0.0667	−0.0569	−0.803	0.669	−0.686	0.572
	251.1	247	247	30	−0.467	−0.189	−1.68	0.746	−0.680	0.302
Hemoglobin, hemolysate, 1000	59.0	59.6	58	30	−1.67	−2.79	−2.21	−1.12	−3.70	−1.88
	124.7	125	123	30	−1.90	−1.52	−2.71	−1.09	−2.16	−0.869
	262.7	264	261	30	−2.67	−1.01	−4.13	−1.20	−1.56	−0.456
Hemoglobin, lyophilizate, 1000	62.6	63.4	62.6	30	−0.800	−1.26	−2.72	1.12	−4.30	1.77
	126.9	129	126	30	−2.87	−2.22	−3.69	−2.04	−2.86	−1.58
	258.4	260	256	30	−4.53	−1.74	−5.97	−3.09	−2.30	−1.19
Insulin, 127 mU/L	59.3	59.0	58.0	30	−1.00	−1.70	−1.53	−0.475	−2.59	−0.805
	122.4	121	121	30	−0.733	−0.604	−1.43	−0.0368	−1.18	−0.0303
	259.5	261	261	30	−0.133	−0.0511	−1.33	1.06	−0.509	0.407
Intralipid/triglycerides, 2000/1500	63.5	62.0	59.9	30	−2.10	−3.39	−2.70	−1.50	−4.36	−2.42
	134.2	133	128	30	−4.80	−3.61	−5.45	−4.15	−4.10	−3.12
	262.1	258	253	30	−4.80	−1.86	−5.67	−3.93	−2.20	−1.52
Lactate, 200	59.3	58.9	59.5	30	0.633	1.08	0.188	1.08	0.320	1.83
	114.0	114	115	30	0.700	0.613	0.0868	1.31	0.0761	1.15
	253.7	255	254	30	−0.967	−0.379	−2.14	0.205	−0.837	0.0803
Magnesium, 10	59.3	58.9	58.3	30	−0.533	−0.906	−0.918	−0.149	−1.56	−0.252
	114.0	114	114	30	−0.400	−0.350	−1.07	0.270	−0.937	0.237
	253.7	255	255	30	−0.233	−0.0914	−1.59	1.12	−0.622	0.439
Maltose, 480^a	58.6	58.8	60	30	1.17	1.98	0.677	1.66	1.15	2.82
	120.8	119	120	30	1.23	1.04	0.538	1.93	0.454	1.62
	249.2	247	248	30	0.900	0.364	−1.15	2.95	−0.466	1.19
Mannose, 500	58.6	58.8	59.8	30	0.933	1.59	0.359	1.51	0.611	2.56
	120.8	119	120	30	1.40	1.18	0.616	2.18	0.519	1.84
	249.2	247	249	30	1.63	0.661	0.0993	3.17	0.0402	1.28
Phosphate, 12	59.3	58.9	58.1	30	−0.767	−1.30	−1.15	−0.382	−1.96	−0.649
	114.0	114	113	30	−1.30	−1.14	−2.04	−0.558	−1.79	−0.489
	253.7	255	254	30	−0.867	−0.339	−2.01	0.274	−0.786	0.107
Potassium (chloride), 8 mmol/L	59.3	59.0	56.9	30	−2.03	−3.45	−2.54	−1.52	−4.32	−2.58
	122.4	121	119	30	−2.47	−2.03	−3.18	−1.75	−2.62	−1.44
	259.5	261	260	30	−0.900	−0.345	−2.04	0.244	−0.783	0.0933
Sodium chloride, 180 mmol/L	61.3	60.9	58.9	30	−1.97	−3.23	−2.53	−1.41	−4.15	−2.31
	124.9	126	124	30	−1.97	−1.56	−2.76	−1.17	−2.20	−0.930
	263.8	264	264	30	0.433	0.164	−0.779	1.65	−0.296	0.625
Urea, 120	58.6	58.8	58.3	30	−0.533	−0.907	−1.09	0.0282	−1.86	0.0479
	120.8	119	118	30	−0.567	−0.477	−1.37	0.236	−1.15	0.199
	249.2	247	246	30	−0.700	−0.283	−2.11	0.708	−0.853	0.287
Uric acid, 23.5	59.5	61.8	61.1	30	−0.667	−1.08	−1.19	−0.141	−1.93	−0.228
	125.7	128	128	30	−0.233	−0.182	−0.962	0.496	−0.749	0.386
	259.0	262	262	30	0.333	0.127	−0.685	1.35	−0.262	0.516

Abbreviations: BG, blood glucose; BGMS, blood glucose monitoring system; CI, confidence interval.

The test strip for the BGMS can be used by patients treated with maltose-containing or maltose-producing therapies thanks to the strip’s new enzyme (flavin adenine dinucleotide-dependent glucose dehydrogenase), which is insensitive to maltose. Icodextrin, used in dialysis solutions, is converted to small glucose polymers (maltose molecules [G2], maltotriose [G3], and maltotetraose [G4]) when administered intraperitoneally for peritoneal dialysis. These polymers are misinterpreted as glucose when using strips susceptible to maltose interference.¹⁵ The BGMS has been tested with maltose concentrations higher than the concentration of the sum of all icodextrin metabolites and did not show any interferences.

Drugs

When compared with control, the mean absolute or relative bias did not exceed ±10 mg/dL or ±10% for any drugs tested with any of the three strip lots. Pooled results for 30 replicates (10 for each of three strip lots tested) are presented in Table 2.

Table 2.

Potential Interference by Drugs Pooled Over Three Test Strip Lots.

Drug, concentration (mg/dL unless stated differently)	BG concentration
Drug, concentration (mg/dL unless stated differently)	Control sample (mg/dL)	Control sample, mean (mg/dL)	Test sample, mean (mg/dL)	Test sample (N)	Absolute bias (mg/dL)	Relative bias (%)	Lower CI for absolute bias (mg/dL)	Upper CI for absolute bias (mg/dL)	Lower CI for relative bias (%)	Upper CI for relative bias (%)
Acetate, 30.1	62.5	61.3	61.2	30	−0.100	−0.163	−0.688	0.488	−1.12	0.796
	129.3	127	127	30	0.0667	0.0526	−1.07	1.21	−0.846	0.951
	254.4	253	254	30	1.03	0.409	−0.877	2.94	−0.347	1.17
Acetaminophen (paracetamol), 20	63.2	62.6	61.8	30	−0.867	−1.38	−1.42	−0.314	−2.27	−0.501
	125.6	123	123	30	−0.367	−0.297	−1.04	0.309	−0.845	0.251
	259.9	258	258	30	−0.633	−0.245	−1.79	0.519	−0.692	0.201
Acetylsalicylic acid, 3	65.4	65.7	65.5	30	−0.233	−0.355	−0.956	0.489	−1.45	0.744
	122.6	124	124	30	−0.500	−0.402	−1.75	0.752	−1.41	0.604
	252.1	256	255	30	−0.367	−0.143	−2.49	1.75	−0.972	0.686
Acyclovir, 6.6	62.3	61.0	61.1	30	0.167	0.273	−0.343	0.676	−0.563	1.11
	126.1	124	124	30	0.0667	0.0537	−0.712	0.845	−0.573	0.681
	259.1	256	256	30	−0.100	−0.0390	−1.51	1.31	−0.588	0.510
Amikacin, 14.4	61.6	60.5	60.9	30	0.433	0.716	−0.156	1.02	−0.258	1.69
	124.3	123	123	30	0.333	0.271	−0.376	1.04	−0.306	0.848
	259.1	258	259	30	0.433	0.168	−0.890	1.76	−0.345	0.680
Amiodarone, 4.2	61.2	56.4	56.7	30	0.300	0.532	−0.186	0.786	−0.329	1.39
	122.1	112	112	30	0.200	0.179	−0.687	1.09	−0.616	0.974
	252.9	224	226	30	1.37	0.609	−0.0124	2.75	−0.00555	1.22
Amoxicillin, 5.4	62.3	61.0	60.7	30	−0.233	−0.383	−0.698	0.231	−1.14	0.379
	126.1	124	124	30	0.00	0.00	−0.763	0.763	−0.614	0.614
	259.1	256	257	30	0.400	0.156	−1.04	1.84	−0.405	0.717
Ampicillin, 7.5	61.6	60.5	60.9	30	0.367	0.606	−0.180	0.914	−0.298	1.51
	124.3	123	123	30	0.333	0.271	−0.420	1.09	−0.342	0.884
	259.1	258	255	30	−2.90	−1.12	−4.18	−1.62	−1.62	−0.626
Anakinra, 30.86	61.6	60.5	60.1	30	−0.400	−0.661	−0.977	0.177	−1.61	0.292
	124.3	123	123	30	−0.400	−0.325	−1.19	0.392	−0.970	0.319
	259.1	258	258	30	−0.100	−0.0387	−1.38	1.18	−0.534	0.456
Anidulafungin, 3.3	64.4	63.1	62.5	30	−0.600	−0.951	−1.32	0.122	−2.10	0.194
	127.2	127	127	30	−0.267	−0.210	−1.51	0.978	−1.19	0.771
	251.2	252	252	30	0.00	0.00	−2.24	2.24	−0.888	0.888
Ascorbic acid (ascorbate), 8	58.9	58.4	59.3	30	0.867	1.48	0.269	1.46	0.460	2.51
	133.8	136	141	30	4.20	3.08	3.50	4.90	2.57	3.59
	251.6	254	260	30	6.70	2.64	5.60	7.80	2.21	3.08
Azithromycin, 1.11	61.2	56.4	56.4	30	0.00	0.00	−0.502	0.502	−0.890	0.890
	122.1	112	112	30	0.0667	0.0598	−0.743	0.876	−0.666	0.785
	252.9	224	225	30	0.933	0.416	−0.195	2.06	−0.0870	0.919
Aztreonam, 72.6	60.0	61.6	62.3	30	0.667	1.08	0.0632	1.27	0.103	2.06
	118.1	118	120	30	1.43	1.21	0.503	2.36	0.426	2.00
	248.4	238	241	30	3.33	1.40	1.96	4.70	0.826	1.98
Benzylpenicillin, 72	63.8	61.1	60.5	30	−0.633	−1.04	−1.13	−0.139	−1.84	−0.228
	128.7	126	124	30	−1.50	−1.19	−2.09	−0.907	−1.66	−0.720
	260.8	260	258	30	−1.97	−0.756	−3.27	−0.661	−1.26	−0.254
Bicarbonate, 62	62.5	61.3	61.3	30	0.00	0.00	−0.624	0.624	−1.02	1.02
	129.3	127	127	30	0.700	0.552	−0.425	1.83	−0.335	1.44
	254.4	253	255	30	2.37	0.937	0.668	4.06	0.265	1.61
Bictegravir, 1.43	61.2	63.0	62.9	30	−0.100	−0.159	−0.653	0.453	−1.04	0.720
	114.5	115	116	30	0.400	0.347	−0.608	1.41	−0.527	1.22
	235.3	236	237	30	1.13	0.480	−1.12	3.38	−0.473	1.43
Bromide, 300	58.3	59.4	59.7	30	0.267	0.449	−0.308	0.841	−0.518	1.42
	121.0	125	123	30	−2.10	−1.67	−2.94	−1.26	−2.34	−1.01
	261.8	263	267	30	3.90	1.48	2.50	5.30	0.951	2.01
Bupivacaine, 1.2	63.8	61.1	60.8	30	−0.367	−0.600	−0.869	0.136	−1.42	0.222
	128.7	126	126	30	−0.300	−0.238	−0.863	0.263	−0.686	0.209
	260.8	260	259	30	−0.900	−0.346	−2.06	0.262	−0.792	0.101
Cafedrine, 1.8	64.4	63.1	62.9	30	−0.200	−0.317	−0.890	0.490	−1.41	0.777
	127.2	127	127	30	−0.133	−0.105	−1.33	1.07	−1.05	0.840
	251.2	252	252	30	0.167	0.0662	−2.24	2.57	−0.888	1.02
Caffeine, 10.8	63.8	61.1	61.0	30	−0.167	−0.273	−0.694	0.361	−1.14	0.590
	128.7	126	125	30	−0.933	−0.742	−1.55	−0.314	−1.23	−0.249
	260.8	260	259	30	−0.967	−0.372	−2.15	0.221	−0.828	0.0849
Calcium gluconate, 120	59.2	56.9	57.6	30	0.633	1.11	0.111	1.16	0.195	2.03
	127.0	123	124	30	0.467	0.379	−0.262	1.19	−0.212	0.970
	259.8	253	254	30	0.667	0.263	−0.547	1.88	−0.216	0.742
Canagliflozin, 1.4	60.0	61.6	61.8	30	0.200	0.325	−0.351	0.751	−0.570	1.22
	118.1	118	118	30	0.267	0.226	−0.582	1.12	−0.492	0.943
	248.4	238	239	30	1.03	0.434	−0.339	2.41	−0.142	1.01
Captopril, 0.265	62.2	59.5	58.5	30	−1.00	−1.68	−1.51	−0.488	−2.54	−0.820
	125.5	123	122	30	−1.23	−1.00	−2.07	−0.395	−1.68	−0.321
	259.5	259	260	30	1.37	0.527	−0.166	2.90	−0.0641	1.12
Carbamazepine, 4.5	61.2	56.4	57.1	30	0.633	1.12	0.157	1.11	0.278	1.97
	122.1	112	111	30	−0.400	−0.359	−1.55	0.755	−1.39	0.677
	252.9	224	225	30	0.633	0.282	−0.408	1.68	−0.182	0.747
Cefaclor, 8.7	59.2	58.3	58.5	30	0.233	0.400	−0.264	0.731	−0.453	1.25
	121.4	120	121	30	1.03	0.859	0.372	1.69	0.309	1.41
	253.7	254	255	30	0.733	0.289	−0.523	1.99	−0.206	0.783
Cefazolin, 45	62.2	59.5	63.7	30	4.13	6.94	3.69	4.57	6.20	7.68
	125.5	123	130	30	6.73	5.46	5.86	7.61	4.75	6.17
	259.5	259	266	30	7.23	2.79	5.65	8.81	2.18	3.40
Cefepime, 48	64.5	66.0	70.6	30	4.67	7.07	4.14	5.19	6.28	7.87
	123.6	126	135	30	8.87	7.04	8.01	9.72	6.36	7.73
	248.6	256	279	30	23.0	9.01	21.9	24.2	8.56	9.47
Cefotaxime, 52.8	62.2	59.5	60.7	30	1.20	2.02	0.743	1.66	1.25	2.78
	125.5	123	126	30	2.37	1.92	1.61	3.12	1.31	2.53
	259.5	259	265	30	5.67	2.19	4.05	7.28	1.56	2.81
Cefoxitin, 600	60.8	59.2	61.1	30	1.93	3.27	1.42	2.45	2.40	4.13
	121.9	122	126	30	4.30	3.52	3.66	4.94	3.00	4.04
	253.1	255	259	30	4.23	1.66	3.13	5.34	1.23	2.10
Ceftazidime, 60.6	62.3	61.0	62.1	30	1.13	1.86	0.665	1.60	1.09	2.63
	126.1	124	125	30	0.700	0.564	−0.0845	1.48	−0.0681	1.20
	259.1	256	252	30	−4.07	−1.59	−5.50	−2.63	−2.14	−1.03
Ceftriaxone, 84	58.3	59.4	59	30	−0.467	−0.785	−1.04	0.102	−1.74	0.172
	121.0	125	123	30	−2.73	−2.18	−3.34	−2.13	−2.66	−1.70
	261.8	263	259	30	−3.97	−1.51	−5.30	−2.63	−2.01	−1.00
Cefuroxime, 54.3	60.8	59.2	58.5	30	−0.633	−1.07	−1.16	−0.109	−1.96	−0.185
	121.9	122	121	30	−1.03	−0.846	−1.87	−0.194	−1.53	−0.159
	253.1	255	254	30	−0.533	−0.209	−1.79	0.726	−0.704	0.285
Celecoxib, 0.879	62.8	59.7	59.9	30	0.200	0.335	−0.384	0.784	−0.644	1.31
	116.3	109	110	30	0.533	0.489	−0.534	1.60	−0.490	1.47
	241.3	228	229	30	1.60	0.703	−0.790	3.99	−0.347	1.75
Chlorothiazide, 2.7	61.8	60.2	60.6	30	0.367	0.609	−0.346	1.08	−0.574	1.79
	121.6	118	118	30	−0.133	−0.113	−0.990	0.724	−0.839	0.613
	251.9	249	249	30	0.133	0.0535	−2.29	2.55	−0.918	1.03
Cimetidine, 3	58.3	59.4	63.4	30	3.93	6.62	3.40	4.47	5.72	7.52
	121.0	125	116	30	−9.37	−7.47	−10.0	−8.69	−8.01	−6.92
	257.6	252	259	30	6.93	2.75	5.55	8.32	2.20	3.30
Clavulanate, 1.2	64.4	63.1	62.8	30	−0.233	−0.370	−1.08	0.609	−1.71	0.966
	127.2	127	127	30	0.200	0.158	−1.04	1.44	−0.819	1.13
	251.2	252	252	30	0.00	0.00	−2.24	2.24	−0.889	0.889
Clindamycin, 5.1	60.8	59.2	58.5	30	−0.700	−1.18	−1.22	−0.185	−2.05	−0.312
	121.9	122	120	30	−1.97	−1.61	−3.52	−0.410	−2.88	−0.335
	253.1	255	256	30	0.800	0.314	−0.366	1.97	−0.144	0.771
Clopidogrel carboxylic acid, 3.67	60.9	63.3	63.8	30	0.567	0.896	−0.177	1.31	−0.280	2.07
	113.8	115	115	30	−0.200	−0.174	−1.23	0.827	−1.06	0.717
	237.9	237	237	30	0.367	0.155	−1.81	2.54	−0.765	1.07
Cyclosporin A, 0.18	60.6	56.8	56.7	30	−0.133	−0.235	−0.630	0.363	−1.11	0.639
	120.9	111	111	30	0.0667	0.0598	−0.697	0.830	−0.626	0.745
	251.1	224	226	30	1.60	0.714	0.398	2.80	0.178	1.25
Dexamethasone, 1.2	60.0	61.6	61.5	30	−0.0667	−0.108	−0.568	0.435	−0.923	0.706
	118.1	118	119	30	0.367	0.310	−0.529	1.26	−0.448	1.07
	248.4	238	238	30	−0.167	−0.0700	−1.51	1.18	−0.635	0.495
Diazepam, 3	60.6	59.4	58.8	30	−0.633	−1.07	−1.23	−0.0333	−2.08	−0.0561
	119.8	116	116	30	0.600	0.518	−0.138	1.34	−0.119	1.15
	251.5	235	236	30	1.73	0.739	0.476	2.99	0.203	1.28
Diclofenac, 2.4	57.7	55.1	54.7	30	−0.400	−0.726	−0.931	0.131	−1.69	0.238
	121.9	118	118	30	−0.500	−0.423	−1.37	0.372	−1.16	0.314
	258.3	256	256	30	−0.867	−0.338	−2.63	0.901	−1.03	0.351
Dipyridamole, 3.54	59.2	58.3	54.5	30	−3.80	−6.52	−4.29	−3.31	−7.36	−5.68
	121.4	120	114	30	−6.53	−5.43	−7.16	−5.91	−5.95	−4.91
	253.7	254	241	30	−13.2	−5.20	−14.5	−11.9	−5.71	−4.68
Docusate, 2.37	61.2	60.8	59.9	30	−0.867	−1.43	−1.84	0.103	−3.02	0.169
	122.0	121	121	30	−0.533	−0.440	−1.67	0.601	−1.38	0.496
	250.7	250	249	30	−0.167	−0.0668	−1.96	1.62	−0.784	0.651
Dopamine, 0.09	65.8	64.8	65.1	30	0.267	0.411	−0.373	0.906	−0.575	1.40
	129.1	127	127	30	−0.100	−0.0788	−0.851	0.651	−0.670	0.513
	263.1	262	261	30	−0.900	−0.344	−1.89	0.0854	−0.721	0.0326
Doxycycline, 1.8	54.8	53.9	53.6	30	−0.267	−0.495	−0.817	0.283	−1.52	0.526
	132.1	130	130	30	0.333	0.257	−0.364	1.03	−0.281	0.796
	264.0	263	262	30	−0.300	−0.114	−1.85	1.25	−0.704	0.476
D-Sorbitol, 70	63.2	62.6	62.6	30	0.00	0.00	−0.591	0.591	−0.944	0.944
	125.6	123	124	30	0.200	0.162	−0.473	0.873	−0.383	0.707
	259.9	258	258	30	0.200	0.0774	−1.00	1.40	−0.389	0.544
EDTA, 0.1	59.1	57.3	57.3	30	0.00	0.00	−0.473	0.473	−0.826	0.826
	123.4	122	122	30	−0.167	−0.137	−0.827	0.493	−0.677	0.404
	259.7	257	257	30	−0.333	−0.130	−1.58	0.910	−0.613	0.354
Emtricitabine, 0.9	57.4	55.2	55.3	30	0.167	0.302	−0.413	0.746	−0.748	1.35
	118.3	117	117	30	0.00	0.00	−1.05	1.05	−0.904	0.904
	254.7	252	252	30	0.567	0.225	−1.70	2.84	−0.677	1.13
Enoxaparin, 435 IU/dL	54.8	53.9	53.3	30	−0.567	−1.05	−1.12	−0.00965	−2.08	−0.0179
	132.1	130	129	30	−0.300	−0.232	−1.04	0.438	−0.802	0.338
	264.0	263	261	30	−1.17	−0.444	−2.57	0.241	−0.980	0.0919
Ephedrine, 1	60.6	59.4	59.3	30	−0.167	−0.280	−0.706	0.373	−1.19	0.628
	119.8	116	116	30	0.233	0.201	−0.570	1.04	−0.492	0.895
	251.5	235	235	30	0.200	0.0853	−1.08	1.48	−0.460	0.631
Erythromycin, 13.8	54.8	53.9	53.3	30	−0.600	−1.11	−1.17	−0.0282	−2.17	−0.0523
	132.1	130	129	30	−0.0667	−0.0515	−0.788	0.654	−0.608	0.505
	264.0	263	263	30	−0.100	−0.0381	−1.54	1.34	−0.588	0.512
Esmolol, 0.48	66.3	64.9	64.8	30	−0.0667	−0.103	−0.605	0.471	−0.932	0.726
	129.6	128	127	30	−0.300	−0.235	−1.06	0.463	−0.833	0.363
	264.8	261	261	30	−0.167	−0.0639	−1.27	0.940	−0.488	0.360
Ethanol, 600	66.3	64.9	64.6	30	−0.267	−0.411	−0.800	0.266	−1.23	0.410
	129.6	128	122	30	−5.17	−4.05	−5.84	−4.49	−4.58	−3.52
	264.8	261	249	30	−11.7	−4.48	−13.1	−10.3	−5.02	−3.93
Fe(II) (sulfate), 0.879	60.6	60.3	60.8	30	0.500	0.829	−0.189	1.19	−0.314	1.97
	126.2	128	127	30	−0.400	−0.313	−1.24	0.443	−0.974	0.347
	269.5	269	268	30	−0.133	−0.0496	−1.33	1.07	−0.496	0.397
Fenofibrate, 4.5	60.6	56.8	56.9	30	0.133	0.235	−0.421	0.687	−0.741	1.21
	120.9	111	111	30	−0.200	−0.180	−0.980	0.580	−0.879	0.520
	251.1	224	226	30	1.77	0.788	0.619	2.91	0.276	1.30
Flecainide, 0.513	57.4	55.2	55.0	30	−0.200	−0.363	−0.731	0.331	−1.32	0.599
	118.3	117	117	30	0.467	0.400	−0.498	1.43	−0.427	1.23
	254.7	252	252	30	−0.233	−0.0927	−2.65	2.18	−1.05	0.866
Fluconazole, 2.55	66.3	64.9	65.0	30	0.100	0.154	−0.402	0.602	−0.619	0.927
	129.6	128	127	30	−0.667	−0.523	−1.33	−0.00289	−1.04	−0.00226
	264.8	261	260	30	−0.667	−0.256	−1.97	0.641	−0.757	0.246
5-Fluorouracil, 9	62.4	61.9	60.8	30	−1.10	−1.78	−2.03	−0.169	−3.28	−0.274
	118.2	118	120	30	1.57	1.33	−1.60	4.73	−1.35	4.01
	249.5	252	251	30	−1.63	−0.647	−3.76	0.490	−1.49	0.194
Fosinopril, 1.68	62.4	61.9	61.2	30	−0.767	−1.24	−1.76	0.226	−2.84	0.365
	118.2	118	118	30	0.0333	0.0283	−0.971	1.04	−0.823	0.880
	249.5	252	252	30	−0.300	−0.119	−2.55	1.95	−1.01	0.774
Fosphenytoin, 38.7	62.5	62.0	61.3	30	−0.667	−1.08	−1.16	−0.171	−1.88	−0.277
	123.2	125	124	30	−0.933	−0.748	−1.65	−0.219	−1.32	−0.176
	257.2	258	257	30	−0.933	−0.361	−2.20	0.334	−0.852	0.129
Furosemide, 1.59	59.1	57.3	57.4	30	0.133	0.233	−0.408	0.675	−0.712	1.18
	123.4	122	122	30	0.133	0.109	−0.491	0.758	−0.402	0.621
	259.7	257	258	30	0.433	0.168	−0.636	1.50	−0.247	0.584
Fusidate, 60	63.6	63.7	62.6	30	−1.17	−1.83	−2.08	−0.253	−3.26	−0.397
	121.1	123	120	30	−2.30	−1.87	−3.51	−1.09	−2.86	−0.892
	252.5	256	253	30	−3.73	−1.46	−6.43	−1.03	−2.51	−0.404
Gabapentin, 2.67	62.5	62.0	61.5	30	−0.433	−0.699	−0.886	0.0190	−1.43	0.0307
	123.2	125	124	30	−0.500	−0.401	−1.22	0.216	−0.975	0.173
	257.2	258	258	30	−0.267	−0.103	−1.55	1.02	−0.600	0.394
Gentamicin, 3	62.5	62.0	63.6	30	1.67	2.69	1.17	2.17	1.89	3.49
	123.2	125	126	30	1.23	0.989	0.506	1.96	0.406	1.57
	257.2	258	262	30	3.23	1.25	1.90	4.56	0.737	1.77
Gentisic acid, 2	65.8	64.8	64.9	30	0.0333	0.0514	−0.565	0.631	−0.871	0.974
	129.1	127	127	30	−0.267	−0.210	−0.976	0.443	−0.769	0.349
	263.1	262	253	30	−8.53	−3.26	−9.54	−7.52	−3.65	−2.88
Gliclazid, 1.11	59.3	62.0	62.4	30	0.400	0.646	−0.151	0.951	−0.244	1.53
	119.2	118	119	30	0.400	0.339	−0.435	1.24	−0.368	1.05
	244.7	239	239	30	−0.500	−0.209	−1.80	0.804	−0.754	0.336
γ-Globulin, human, 1600	62.4	61.9	60.2	30	−1.77	−2.85	−2.75	−0.788	−4.43	−1.27
	118.2	118	116	30	−2.07	−1.75	−3.11	−1.03	−2.64	−0.870
	249.5	252	249	30	−3.10	−1.23	−5.29	−0.911	−2.09	−0.361
Guaifenesin, 0.45	57.3	56.9	56.8	30	−0.0667	−0.117	−0.719	0.585	−1.26	1.03
	119.5	120	120	30	0.00	0.00	−1.06	1.06	−0.889	0.889
	246.9	249	249	30	0.567	0.228	−1.46	2.59	−0.587	1.04
Heparin, 330 IU/dL	59.9	59.7	59.9	30	0.167	0.279	−0.261	0.595	−0.438	0.996
	122.4	123	124	30	0.400	0.325	−0.237	1.04	−0.192	0.841
	247.2	249	248	30	−0.733	−0.294	−1.76	0.298	−0.708	0.119
HES, 3600	57.6	65.1	59.5	30	−5.57	−8.55	−6.13	−5.01	−9.41	−7.69
	112.3	124	113	30	−11.1	−9.00	−12.0	−10.2	−9.74	−8.26
	247.8	260	246	30	−14.3	−5.49	−15.6	−12.9	−6.01	−4.96
Hydralazine, 1.44	59.9	59.7	65.8	30	6.07	10.2	5.61	6.53	9.39	10.9
	122.4	123	133	30	9.67	7.85	8.82	10.5	7.16	8.53
	247.2	249	266	30	16.7	6.70	15.5	17.9	6.23	7.17
Hydroxychloroquine, 0.731	57.3	56.9	57.6	30	0.767	1.35	0.00358	1.53	0.00630	2.69
	119.5	120	121	30	1.63	1.37	0.437	2.83	0.365	2.37
	246.9	249	249	30	0.267	0.107	−1.81	2.34	−0.727	0.941
Ibuprofen, 50	59.1	57.3	55.0	30	−2.30	−4.01	−2.85	−1.75	−4.98	−3.05
	123.4	122	119	30	−3.40	−2.79	−4.06	−2.74	−3.33	−2.24
	259.7	257	251	30	−6.17	−2.40	−7.20	−5.14	−2.80	−2.00
Iohexol, 35.7	59.9	59.7	59.1	30	−0.600	−1.01	−1.03	−0.165	−1.73	−0.277
	122.4	123	123	30	−0.200	−0.162	−0.895	0.495	−0.726	0.402
	247.2	249	249	30	−0.700	−0.281	−1.84	0.441	−0.739	0.177
Ipragliflozin, 0.52	60.6	56.8	57.2	30	0.367	0.646	−0.180	0.914	−0.317	1.61
	120.9	111	111	30	−0.533	−0.479	−1.31	0.242	−1.18	0.218
	251.1	224	226	30	1.67	0.743	0.269	3.06	0.120	1.37
Irbesartan, 2.31	61.8	64.0	63.7	30	−0.367	−0.573	−0.995	0.261	−1.55	0.408
	116.2	116	116	30	0.267	0.230	−0.710	1.24	−0.614	1.07
	238.1	238	237	30	−0.567	−0.238	−2.40	1.27	−1.01	0.534
Iron saccharate, 3	63.6	63.7	63.9	30	0.200	0.314	−0.806	1.21	−1.26	1.89
	121.1	123	123	30	0.300	0.244	−1.03	1.63	−0.843	1.33
	252.5	256	256	30	−0.600	−0.234	−3.44	2.24	−1.34	0.874
Isomalt, 100	61.3	60.7	61.1	30	0.367	0.604	−0.123	0.857	−0.203	1.41
	123.6	124	124	30	0.233	0.188	−0.479	0.946	−0.387	0.763
	256.5	257	258	30	0.933	0.364	−0.403	2.27	−0.157	0.884
Isosorbide dinitrate, 0.593	59.3	62.0	62.1	30	0.100	0.161	−0.463	0.663	−0.747	1.07
	119.2	118	118	30	0.100	0.0846	−0.697	0.897	−0.590	0.759
	244.7	239	240	30	0.367	0.153	−0.937	1.67	−0.391	0.698
Isosorbide mononitrate, 0.221	60.6	59.1	59.3	30	0.267	0.451	−0.327	0.860	−0.554	1.46
	119.1	117	117	30	0.00	0.00	−1.00	1.00	−0.855	0.855
	252.1	248	247	30	−0.200	−0.0808	−2.28	1.88	−0.919	0.758
Ketamine, 1.89	60.6	59.1	59.3	30	0.233	0.395	−0.425	0.892	−0.720	1.51
	119.1	117	118	30	0.467	0.397	−0.552	1.49	−0.470	1.26
	252.1	248	248	30	0.467	0.188	−1.66	2.59	−0.669	1.05
Ketoprofen, 6	60.4	60.7	60.6	30	−0.100	−0.165	−0.715	0.515	−1.18	0.848
	125.6	125	125	30	−0.367	−0.293	−1.13	0.392	−0.899	0.313
	256.5	258	257	30	−0.933	−0.361	−1.96	0.0906	−0.758	0.0351
Ketorolac, 2.055	61.3	60.7	60.3	30	−0.433	−0.714	−0.914	0.0473	−1.51	0.0780
	123.6	124	124	30	0.300	0.242	−0.429	1.03	−0.347	0.831
	256.5	257	256	30	−0.167	−0.0649	−1.45	1.12	−0.565	0.435
Lacosamide, 2.61	61.3	60.7	60.2	30	−0.467	−0.769	−0.945	0.0116	−1.56	0.0191
	123.6	124	123	30	−1.03	−0.834	−1.73	−0.334	−1.40	−0.270
	256.5	257	257	30	0.00	0.00	−1.28	1.28	−0.498	0.498
Lactitol, 100	60.3	59.7	59.4	30	−0.300	−0.503	−0.806	0.206	−1.35	0.344
	123.1	123	124	30	1.10	0.897	0.463	1.74	0.378	1.42
	256.4	259	260	30	0.300	0.116	−0.935	1.54	−0.361	0.592
Lactose, 500	60.3	59.7	60.1	30	0.367	0.614	−0.133	0.866	−0.222	1.45
	123.1	123	124	30	1.63	1.33	0.883	2.38	0.721	1.94
	256.4	259	262	30	2.27	0.874	1.01	3.52	0.391	1.36
Lansoprazole, 20	60.3	56.6	57.4	30	0.767	1.35	0.198	1.34	0.350	2.36
	121.5	111	113	30	1.10	0.987	0.324	1.88	0.290	1.68
	254.0	226	228	30	1.97	0.871	0.687	3.25	0.304	1.44
L-Leucine, 2.82	57.3	56.9	56.7	30	−0.200	−0.352	−0.822	0.422	−1.45	0.743
	119.5	120	119	30	−0.467	−0.391	−1.62	0.682	−1.35	0.571
	246.9	249	249	30	−0.133	−0.0536	−1.89	1.62	−0.759	0.652
Levetiracetam, 27	60.3	59.7	59.1	30	−0.600	−1.01	−1.09	−0.106	−1.83	−0.177
	123.1	123	122	30	−0.567	−0.462	−1.21	0.0749	−0.986	0.0611
	256.4	259	259	30	0.0333	0.0129	−1.13	1.19	−0.435	0.460
Levodopa (L-Dopa), 0.75	62.1	60.4	60.3	30	−0.0333	−0.0552	−0.566	0.499	−0.938	0.827
	126.0	123	124	30	0.500	0.406	−0.355	1.36	−0.288	1.10
	251.4	252	252	30	−0.433	−0.172	−1.91	1.05	−0.759	0.415
Levofloxacin, 3.6	62.1	60.4	60.0	30	−0.367	−0.607	−0.992	0.259	−1.64	0.429
	126.0	123	124	30	0.667	0.541	−0.0778	1.41	−0.0632	1.15
	251.4	252	252	30	−0.167	−0.0661	−1.37	1.04	−0.543	0.411
Lidocaine, 1.5	62.1	60.4	59.7	30	−0.667	−1.10	−1.18	−0.153	−1.96	−0.254
	126.0	123	124	30	0.367	0.298	−0.496	1.23	−0.403	0.998
	251.4	252	253	30	0.633	0.251	−0.688	1.95	−0.273	0.775
Lopinavir/ritonavir, 4.05/1.0125	60.3	56.6	57.2	30	0.567	1.00	0.0180	1.12	0.0318	1.97
	121.5	111	111	30	−0.333	−0.299	−1.08	0.413	−0.969	0.370
	254.0	226	226	30	0.200	0.0885	−1.04	1.44	−0.458	0.635
Maltitol, 20.2	58.6	56.9	56.7	30	−0.133	−0.234	−0.714	0.448	−1.26	0.787
	121.7	120	120	30	−0.133	−0.111	−0.747	0.480	−0.624	0.401
	256.1	257	256	30	−1.20	−0.466	−2.58	0.178	−1.00	0.0691
Mannitol, 1800	56.7	56.7	58.3	30	1.67	2.94	0.990	2.34	1.75	4.13
	117.4	118	121	30	2.63	2.23	1.81	3.46	1.53	2.93
	250.8	251	254	30	2.40	0.956	1.29	3.51	0.513	1.40
Meropenem, 33.9	58.6	56.9	56.4	30	−0.500	−0.879	−1.12	0.116	−1.96	0.204
	121.7	120	120	30	0.0667	0.0557	−0.676	0.809	−0.565	0.676
	256.1	257	257	30	−0.100	−0.0389	−1.32	1.12	−0.512	0.434
Metamizole sodium, 3.3	61.2	59.6	59.2	30	−0.433	−0.727	−1.24	0.369	−2.07	0.619
	119.8	117	117	30	−0.267	−0.228	−1.49	0.953	−1.27	0.814
	243.9	241	241	30	−0.600	−0.249	−2.63	1.43	−1.09	0.593
Metformin, 1.2	58.6	56.9	56.4	30	−0.467	−0.821	−1.03	0.0957	−1.81	0.168
	121.7	120	119	30	−0.233	−0.195	−1.01	0.546	−0.846	0.456
	256.1	257	256	30	−0.867	−0.337	−2.30	0.567	−0.894	0.220
Methadone, 0.318	66.7	61.8	62.2	30	0.433	0.701	−0.0473	0.914	−0.0766	1.48
	120.1	114	114	30	0.0667	0.0583	−0.613	0.746	−0.536	0.653
	249.0	239	238	30	−0.367	−0.154	−2.14	1.41	−0.897	0.589
L-Methionine, 0.9	61.2	59.6	59.5	30	−0.167	−0.279	−1.03	0.698	−1.73	1.17
	119.8	117	118	30	0.967	0.825	−0.221	2.15	−0.189	1.84
	243.9	241	244	30	3.17	1.31	0.992	5.34	0.411	2.21
Methocarbamol, 12.3	62.1	59.7	59.6	30	−0.0667	−0.112	−0.816	0.683	−1.37	1.14
	116.7	109	109	30	0.300	0.275	−0.746	1.35	−0.685	1.24
	242.6	229	229	30	0.333	0.146	−1.35	2.02	−0.592	0.883
Methotrexate, 136	60.4	60.7	56.3	30	−4.40	−7.25	−4.89	−3.91	−8.06	−6.44
	125.6	125	119	30	−6.13	−4.90	−6.92	−5.35	−5.52	−4.27
	256.5	258	251	30	−7.60	−2.94	−8.89	−6.31	−3.44	−2.44
Methyldopa, 2.25	61.8	61.7	62.4	30	0.633	1.03	0.131	1.14	0.212	1.84
	125.3	125	125	30	0.567	0.454	−0.162	1.30	−0.130	1.04
	257.7	261	263	30	1.73	0.664	0.707	2.76	0.271	1.06
Methylprednisolone, 0.783	60.4	60.7	60.3	30	−0.333	−0.549	−0.829	0.162	−1.37	0.267
	125.6	125	125	30	−0.367	−0.293	−0.946	0.213	−0.756	0.170
	256.5	258	256	30	−1.77	−0.684	−2.93	−0.605	−1.13	−0.234
Metronidazole, 12.3	59.2	58.3	58.0	30	−0.333	−0.572	−0.856	0.189	−1.47	0.324
	121.4	120	120	30	0.0333	0.0277	−0.635	0.702	−0.528	0.583
	253.7	254	253	30	−0.833	−0.328	−1.97	0.305	−0.776	0.120
Micafungin, 6.6	61.8	61.7	61.2	30	−0.533	−0.864	−1.03	−0.0408	−1.66	−0.0661
	125.3	125	123	30	−1.77	−1.42	−2.50	−1.04	−2.00	−0.830
	257.7	261	257	30	−4.33	−1.66	−5.54	−3.13	−2.12	−1.20
Midazolam, 0.376	60.6	59.4	59.3	30	−0.100	−0.168	−0.626	0.426	−1.05	0.716
	119.8	116	117	30	0.933	0.805	0.175	1.69	0.151	1.46
	251.5	235	236	30	1.27	0.540	0.151	2.38	0.0644	1.02
Morphine, 0.78	61.0	59.4	59.5	30	0.0333	0.0561	−0.513	0.580	−0.863	0.976
	121.1	116	116	30	−0.467	−0.402	−1.25	0.319	−1.08	0.275
	251.5	235	235	30	−0.267	−0.114	−1.60	1.06	−0.680	0.453
Mycophenolate, 4.2	56.4	57.0	56.7	30	−0.267	−0.468	−0.670	0.136	−1.18	0.239
	121.9	123	122	30	−0.233	−0.190	−1.01	0.547	−0.826	0.446
	257.0	256	256	30	−0.0667	−0.0260	−1.26	1.13	−0.493	0.441
N-acetyl-L-cysteine, 15	58.9	58.4	56.8	30	−1.67	−2.85	−2.35	−0.986	−4.02	−1.69
	133.8	136	136	30	−0.200	−0.147	−1.44	1.04	−1.05	0.762
	251.6	254	247	30	−6.13	−2.42	−7.76	−4.51	−3.06	−1.78
Nafcillin, 11.1	61.8	61.7	61.8	30	0.0333	0.0540	−0.471	0.538	−0.763	0.871
	125.3	125	125	30	0.133	0.107	−0.723	0.989	−0.579	0.793
	257.7	261	261	30	0.267	0.102	−0.943	1.48	−0.361	0.565
Naproxen, 36	58.5	59.2	58.7	30	−0.467	−0.789	−0.939	0.00579	−1.59	0.00979
	122.7	122	122	30	−0.167	−0.136	−0.839	0.506	−0.685	0.413
	262.9	262	259	30	−3.17	−1.21	−4.43	−1.91	−1.69	−0.728
Nateglinide, 4.86	56.4	57.0	56.7	30	−0.233	−0.410	−0.677	0.211	−1.19	0.370
	121.9	123	122	30	−0.600	−0.489	−1.49	0.290	−1.21	0.236
	257.0	256	257	30	0.333	0.130	−0.856	1.52	−0.334	0.594
Neomycin, 1.2	68.2	66.6	67.1	30	0.500	0.751	−0.229	1.23	−0.343	1.85
	123.6	122	123	30	1.30	1.06	0.123	2.48	0.101	2.03
	259.2	259	261	30	2.23	0.863	−0.160	4.63	−0.0617	1.79
Nicotinic acid (sorbinicate metabolite), 4.23	60.6	59.1	58.9	30	−0.200	−0.339	−0.812	0.412	−1.37	0.698
	119.1	117	117	30	−0.600	−0.511	−1.68	0.479	−1.43	0.408
	252.1	248	248	30	0.233	0.0942	−2.07	2.54	−0.836	1.02
Omeprazole, 0.84	59.8	59.3	59.1	30	−0.233	−0.393	−1.01	0.544	−1.70	0.918
	118.0	118	119	30	0.0667	0.0563	−1.16	1.29	−0.979	1.09
	246.4	250	250	30	−0.0333	−0.0133	−2.37	2.30	−0.947	0.921
PAM, 25	57.5	57.5	58.4	30	0.933	1.62	0.316	1.55	0.549	2.70
	116.8	119	119	30	0.700	0.589	−0.441	1.84	−0.372	1.55
	252.6	252	252	30	0.167	0.0661	−1.71	2.05	−0.680	0.812
Pancuronium bromide, 0.4	58.5	59.2	59.0	30	−0.133	−0.225	−0.664	0.397	−1.12	0.671
	122.7	122	122	30	−0.0333	−0.0272	−0.688	0.621	−0.561	0.507
	262.9	262	262	30	0.00	0.00	−1.09	1.09	−0.418	0.418
Pantoprazole, 3	63.2	62.6	61.7	30	−0.967	−1.54	−1.51	−0.425	−2.41	−0.679
	125.6	123	123	30	−0.333	−0.270	−1.15	0.487	−0.935	0.394
	259.9	258	258	30	−0.200	−0.0774	−1.44	1.04	−0.557	0.402
Phenobarbital, 69	61.0	59.4	56.3	30	−3.13	−5.27	−3.74	−2.53	−6.29	−4.25
	121.1	116	112	30	−4.10	−3.53	−4.88	−3.32	−4.20	−2.86
	251.5	235	227	30	−7.40	−3.15	−8.70	−6.10	−3.70	−2.60
Phenol, 4.6	68.2	66.6	65.5	30	−1.03	−1.55	−1.70	−0.366	−2.56	−0.549
	123.6	122	121	30	−0.767	−0.628	−1.93	0.393	−1.58	0.322
	259.2	259	258	30	−0.733	−0.283	−3.11	1.64	−1.20	0.634
L-Phenylalanine, 2.23	61.2	59.6	59.3	30	−0.300	−0.503	−1.13	0.530	−1.90	0.889
	119.8	117	117	30	−0.0667	−0.0569	−1.31	1.18	−1.12	1.00
	243.9	241	242	30	0.633	0.263	−1.28	2.55	−0.532	1.06
Phenylbutazone, 32.1	56.4	57.0	50.7	30	−6.30	−11.1	−6.75	−5.85	−11.8	−10.3
	123.8	128	121	30	−6.60	−5.17	−7.38	−5.82	−5.79	−4.56
	257.0	256	234	30	−22.4	−8.74	−23.6	−21.2	−9.21	−8.27
Phytomenadione, 0.534	62.1	59.7	59.6	30	−0.0333	−0.0559	−0.788	0.721	−1.32	1.21
	116.7	109	109	30	0.100	0.0918	−0.711	0.911	−0.653	0.836
	242.6	229	228	30	−0.567	−0.248	−2.46	1.33	−1.08	0.582
Pioglitazone, 0.476	66.7	61.8	62.6	30	0.767	1.24	0.174	1.36	0.282	2.20
	120.1	114	115	30	0.433	0.379	−0.334	1.20	−0.292	1.05
	249.0	239	238	30	−0.500	−0.210	−2.32	1.32	−0.972	0.553
Piperacillin, 110	58.5	59.2	58.5	30	−0.633	−1.07	−1.19	−0.0752	−2.01	−0.127
	122.7	122	122	30	−0.133	−0.109	−0.807	0.540	−0.659	0.441
	262.9	262	262	30	0.267	0.102	−0.881	1.41	−0.336	0.540
Pirfenidone, 3.78	62.6	62.3	61.5	30	−0.833	−1.34	−1.32	−0.343	−2.12	−0.551
	125.7	125	125	30	−0.267	−0.213	−1.01	0.474	−0.806	0.380
	258.3	255	254	30	−0.533	−0.209	−1.73	0.662	−0.678	0.260
Pregabalin, 2.25	59.8	59.3	59.1	30	−0.267	−0.449	−0.947	0.414	−1.60	0.697
	118.0	118	119	30	0.300	0.253	−0.864	1.46	−0.729	1.24
	246.4	250	249	30	−1.20	−0.480	−3.52	1.12	−1.41	0.447
Primidone, 5.7	59.8	59.3	57.7	30	−1.63	−2.75	−2.36	−0.906	−3.98	−1.53
	118.0	118	118	30	−0.233	−0.197	−1.42	0.949	−1.19	0.801
	246.4	250	250	30	−0.200	−0.0800	−2.81	2.41	−1.12	0.963
Probenecid, 44.7	55.5	55.9	52.3	30	−3.63	−6.50	−4.05	−3.21	−7.25	−5.75
	115.0	116	109	30	−7.47	−6.41	−8.04	−6.89	−6.91	−5.92
	255.6	253	239	30	−14.6	−5.75	−15.9	−13.2	−6.28	−5.23
Procainamide, 4.8	59.1	57.9	58.8	30	0.933	1.61	0.362	1.50	0.625	2.60
	119.3	118	119	30	1.27	1.08	0.0938	2.44	0.0797	2.07
	249.6	243	247	30	4.63	1.91	2.37	6.90	0.975	2.84
Propofol, 4.8	60.3	56.6	57.0	30	0.400	0.707	−0.189	0.989	−0.333	1.75
	121.5	111	111	30	−0.600	−0.538	−1.41	0.206	−1.26	0.185
	254.0	226	227	30	1.30	0.576	−0.0634	2.66	−0.0281	1.18
2-pyridyl acetic acid (betahistine metabolite), 0.579	62.5	61.3	61.3	30	−0.0333	−0.0544	−0.656	0.589	−1.07	0.961
	And 129.3	127	127	30	0.200	0.158	−0.770	1.17	−0.607	0.923
	254.4	253	254	30	1.77	0.699	−0.305	3.84	−0.121	1.52
Quinidine, 1.5	59.1	57.9	57.4	30	−0.533	−0.921	−1.16	0.0948	−2.01	0.164
	119.3	118	118	30	−0.300	−0.255	−1.37	0.769	−1.16	0.653
	249.6	243	244	30	1.67	0.687	−0.327	3.66	−0.135	1.51
Ranitidine, 1.05	62.6	62.3	66.2	30	3.87	6.20	3.28	4.45	5.27	7.14
	125.7	125	130	30	4.53	3.63	3.81	5.26	3.05	4.21
	258.3	255	260	30	4.77	1.87	3.38	6.15	1.33	2.41
Remdesivir, 1.63	60.5	56.9	56.9	30	0.00	0.00	−0.475	0.475	−0.835	0.835
	121.4	111	111	30	−0.0667	−0.0600	−0.744	0.611	−0.670	0.550
	253.4	225	228	30	2.30	1.02	1.01	3.59	0.447	1.60
Rifampicin, 4.8	62.4	62.0	61.8	30	−0.167	−0.269	−0.675	0.342	−1.09	0.552
	124.0	124	124	30	−0.467	−0.375	−1.24	0.308	−0.998	0.248
	256.3	258	258	30	−0.400	−0.155	−1.78	0.983	−0.690	0.380
Rocuronium bromide, 1.8	62.6	62.3	62.2	30	−0.133	−0.214	−0.657	0.390	−1.05	0.626
	125.7	125	125	30	−0.267	−0.213	−1.04	0.505	−0.831	0.404
	258.3	255	255	30	−0.467	−0.183	−1.75	0.822	−0.688	0.322
Salicylate, 60	59.4	60.4	59.0	30	−1.43	−2.37	−1.88	−0.986	−3.11	−1.63
	126.8	127	124	30	−3.47	−2.72	−4.15	−2.78	−3.26	−2.18
	255.6	258	251	30	−7.00	−2.71	−8.36	−5.64	−3.24	−2.19
Sodium fluoride, 0.12	63.6	63.7	63.9	30	0.167	0.262	−0.709	1.04	−1.11	1.64
	121.1	123	123	30	0.0667	0.0543	−1.32	1.45	−1.08	1.18
	252.5	256	257	30	0.433	0.169	−2.27	3.14	−0.887	1.23
Succinylmonocholin chloride (suxamethonium metabolite), 5	60.7	59.5	59.5	30	0.00	0.00	−0.626	0.626	−1.05	1.05
	122.5	121	121	30	−0.333	−0.275	−1.30	0.637	−1.08	0.526
	250.0	250	250	30	−0.0333	−0.0134	−2.37	2.30	−0.949	0.923
Sucrose, 500	59.9	58.3	59.0	30	0.667	1.14	0.171	1.16	0.294	1.99
	125.1	123	124	30	1.67	1.36	0.980	2.35	0.800	1.92
	257.5	254	257	30	3.00	1.18	1.88	4.12	0.741	1.62
Sulbactam, 24	60.7	59.5	60.0	30	0.500	0.840	−0.184	1.18	−0.309	1.99
	122.5	121	121	30	−0.133	−0.110	−1.22	0.951	−1.00	0.785
	250.0	250	251	30	0.967	0.387	−1.25	3.18	−0.501	1.28
Sulfamethoxazole, 40	59.4	60.4	62.9	30	2.43	4.03	1.85	3.02	3.06	5.00
	126.8	127	132	30	4.73	3.72	3.91	5.56	3.07	4.36
	255.6	258	265	30	7.13	2.77	5.89	8.37	2.29	3.25
Tazobactam, 3.05	59.9	58.3	58.2	30	−0.100	−0.172	−0.595	0.395	−1.02	0.677
	125.1	123	123	30	0.167	0.136	−0.551	0.884	−0.450	0.722
	257.5	254	254	30	0.167	0.0657	−0.845	1.18	−0.333	0.464
Tetracycline, 2.4	59.9	58.3	58.0	30	−0.333	−0.572	−0.790	0.123	−1.35	0.211
	125.1	123	123	30	0.400	0.326	−0.220	1.02	−0.179	0.832
	257.5	254	254	30	0.133	0.0525	−0.907	1.17	−0.357	0.462
Thalidomide, 1.03	59.3	62.0	62.0	30	0.0333	0.0538	−0.614	0.681	−0.991	1.10
	119.2	118	119	30	0.667	0.564	−0.250	1.58	−0.211	1.34
	244.7	239	239	30	0.0667	0.0279	−1.35	1.48	−0.565	0.620
Theophylline, 6	59.4	60.4	60.3	30	−0.133	−0.221	−0.621	0.354	−1.03	0.587
	126.8	127	126	30	−0.900	−0.707	−1.69	−0.113	−1.32	−0.0888
	255.6	258	258	30	−0.233	−0.0905	−1.42	0.953	−0.550	0.369
Thiocyanate (nitroprusside metabolite), 5.22	58.7	57.9	55.4	30	−2.53	−4.37	−3.37	−1.69	−5.82	−2.92
	117.8	119	120	30	0.667	0.559	−1.01	2.34	−0.847	1.96
	227.6	234	246	30	11.9	5.08	9.36	14.4	4.00	6.16
Tolazamide, 9	62.5	63.1	63.3	30	0.200	0.317	−0.299	0.699	−0.474	1.11
	122.0	124	124	30	0.133	0.107	−0.605	0.872	−0.488	0.702
	254.8	256	255	30	−0.567	−0.221	−1.66	0.529	−0.650	0.207
Tolbutamide, 72	62.5	63.1	62.6	30	−0.500	−0.792	−0.991	−0.00859	−1.57	−0.0136
	122.0	124	122	30	−2.43	−1.96	−3.15	−1.72	−2.53	−1.39
	254.8	256	251	30	−5.00	−1.95	−5.97	−4.03	−2.33	−1.57
Tramadol, 0.314	64.5	66.0	65.6	30	−0.367	−0.556	−0.893	0.160	−1.35	0.242
	123.6	126	126	30	0.267	0.212	−0.516	1.05	−0.410	0.834
	248.6	256	257	30	1.47	0.574	0.406	2.53	0.159	0.989
Trimethoprim, 4.2	66.7	61.8	65.2	30	3.37	5.45	2.92	3.81	4.73	6.17
	120.1	114	118	30	3.30	2.89	2.62	3.98	2.29	3.48
	249.0	239	249	30	10.1	4.23	8.37	11.8	3.51	4.96
Valproate, 31.8	60.3	60.6	60.7	30	0.0333	0.0550	−0.751	0.818	−1.24	1.35
	120.4	122	122	30	0.167	0.137	−1.11	1.44	−0.911	1.18
	254.8	259	259	30	0.400	0.155	−2.12	2.92	−0.819	1.13
Vancomycin, 12	61.8	60.0	60.1	30	0.0667	0.111	−0.531	0.665	−0.885	1.11
	124.0	124	124	30	−0.533	−0.430	−1.28	0.212	−1.03	0.171
	258.6	260	260	30	−0.200	−0.0770	−1.45	1.05	−0.559	0.405
Warfarin, 7.5	61.8	60.0	60.2	30	0.133	0.222	−0.406	0.673	−0.676	1.12
	124.0	124	123	30	−0.833	−0.672	−1.52	−0.149	−1.22	−0.120
	258.6	260	259	30	−1.17	−0.449	−2.53	0.194	−0.972	0.0745
Xylitol, 200	61.8	60.0	61.1	30	1.03	1.72	0.454	1.61	0.757	2.69
	124.0	124	125	30	1.17	0.941	0.462	1.87	0.373	1.51
	258.6	260	263	30	2.93	1.13	1.60	4.26	0.617	1.64
Xylose, 600	57.5	57.5	65.7	30	8.17	14.2	7.52	8.81	13.1	15.3
	116.8	119	127	30	7.87	6.62	7.12	8.62	5.99	7.26
	252.6	252	263	30	10.9	4.31	9.66	12.1	3.83	4.78
Zonisamide, 11	60.9	63.3	63.7	30	0.467	0.738	−0.276	1.21	−0.436	1.91
	113.8	115	116	30	0.467	0.405	−0.520	1.45	−0.452	1.26
	237.9	237	237	30	0.500	0.211	−1.71	2.71	−0.724	1.15

Abbreviations: BG, blood glucose; CI, confidence interval; EDTA, ethylenediaminetetraacetic acid; HES, hydroxyethyl starch; PAM, pralidoxime iodide.

Hematocrit Level

When compared with results obtained by the plasma-based HK comparator method, the mean absolute or relative bias did not exceed ±10 mg/dL or ±10% for any combination of hematocrit level or glucose concentration over the ranges tested (Table 3). This was also true for the comparison to the nominal hematocrit value of 42% as a control.

Table 3.

Mean Results for the Combination of Hematocrit 5-70% and BG Concentration Range 30-400 mg/dL Pooled Over Three Lots.

Hct (%)	Comparator method (or comparator sample) mean BG (mg/dL)	Test sample (N)	Test (BGMS) mean BG (mg/dL)	Absolute bias (test–comparator) (mg/dL)	Absolute bias due to Hct (mg/dL)	Relative bias (test–comparator) (%)	Relative bias due to Hct (%)	Lower CI for absolute bias (mg/dL)	Upper CI for absolute bias (mg/dL)	Lower CI for relative bias (%)	Upper CI for relative bias (%)
5	30.9	30	31.0	0.0667	−0.633	n.a.	n.a.	−0.307	0.440	n.a.	n.a.
	68.2	30	67.9	−0.267	−1.57	n.a.	n.a.	−0.943	0.409	n.a.	n.a.
	136.5	30	143	n.a.	n.a.	4.42	−0.531	n.a.	n.a.	4.02	4.82
	206.0	30	212	n.a.	n.a.	3.01	0.333	n.a.	n.a.	2.61	3.41
	336.0	30	348	n.a.	n.a.	3.50	0.749	n.a.	n.a.	3.24	3.77
10	29.4	30	29.9	0.533	−0.167	n.a.	n.a.	0.224	0.842	n.a.	n.a.
	66.7	30	66.6	−0.0667	−1.37	n.a.	n.a.	−0.733	0.599	n.a.	n.a.
	135.4	30	143	n.a.	n.a.	5.64	0.687	n.a.	n.a.	5.28	6.00
	205.5	30	210	n.a.	n.a.	2.37	−0.308	n.a.	n.a.	1.99	2.75
	329.2	30	343	n.a.	n.a.	4.12	1.37	n.a.	n.a.	3.67	4.57
15	33.7	30	34.6	0.867	0.167	n.a.	n.a.	0.613	1.12	n.a.	n.a.
	67.9	30	68.7	0.800	−0.500	n.a.	n.a.	0.175	1.42	n.a.	n.a.
	137.5	30	145	n.a.	n.a.	5.67	0.722	n.a.	n.a.	5.25	6.10
	204.8	30	209	n.a.	n.a.	1.95	−0.723	n.a.	n.a.	1.50	2.40
	337.9	30	350	n.a.	n.a.	3.62	0.867	n.a.	n.a.	3.21	4.03
20	33.2	30	33.8	0.633	−0.0667	n.a.	n.a.	0.279	0.988	n.a.	n.a.
	69.0	30	70.0	0.967	−0.333	n.a.	n.a.	0.332	1.60	n.a.	n.a.
	136.4	30	143	n.a.	n.a.	5.06	0.108	n.a.	n.a.	4.63	5.49
	206.1	30	211	n.a.	n.a.	2.30	−0.380	n.a.	n.a.	1.89	2.70
	336.7	30	350	n.a.	n.a.	3.91	1.16	n.a.	n.a.	3.52	4.30
25	46.1	30	46.6	0.533	−0.167	n.a.	n.a.	0.0788	0.988	n.a.	n.a.
	68.0	30	68.7	0.733	−0.567	n.a.	n.a.	0.0354	1.43	n.a.	n.a.
	136.4	30	143	n.a.	n.a.	4.74	−0.210	n.a.	n.a.	4.30	5.18
	206.1	30	210	n.a.	n.a.	1.88	−0.800	n.a.	n.a.	1.42	2.33
	339.4	30	351	n.a.	n.a.	3.35	0.596	n.a.	n.a.	2.94	3.76
30	37.8	30	38.9	1.10	0.400	n.a.	n.a.	0.742	1.46	n.a.	n.a.
	68.4	30	68.8	0.367	−0.933	n.a.	n.a.	−0.356	1.09	n.a.	n.a.
	135.7	30	143	n.a.	n.a.	5.26	0.306	n.a.	n.a.	4.79	5.73
	204.7	30	209	n.a.	n.a.	2.20	−0.478	n.a.	n.a.	1.80	2.59
	331.8	30	341	n.a.	n.a.	2.86	0.110	n.a.	n.a.	2.49	3.24
35	37.6	30	38.3	0.700	0.00	n.a.	n.a.	0.403	0.997	n.a.	n.a.
	69.2	30	70.1	0.900	−0.400	n.a.	n.a.	0.370	1.43	n.a.	n.a.
	136.5	30	143	n.a.	n.a.	4.88	−0.0670	n.a.	n.a.	4.50	5.27
	207.4	30	210	n.a.	n.a.	1.32	−1.36	n.a.	n.a.	0.904	1.73
	325.2	30	335	n.a.	n.a.	3.05	0.302	n.a.	n.a.	2.75	3.36
42	38.2	30	38.9	0.700	0.00	n.a.	n.a.	0.434	0.966	n.a.	n.a.
	67.9	30	69.2	1.30	0.00	n.a.	n.a.	0.822	1.78	n.a.	n.a.
	136.0	30	143	n.a.	n.a.	4.95	0.00	n.a.	n.a.	4.62	5.28
	208.0	30	214	n.a.	n.a.	2.68	0.00	n.a.	n.a.	2.30	3.05
	324.5	30	333	n.a.	n.a.	2.75	0.00	n.a.	n.a.	2.39	3.11
50	37.2	30	37.6	0.433	−0.267	n.a.	n.a.	0.116	0.751	n.a.	n.a.
	67.8	30	68.8	1.00	−0.300	n.a.	n.a.	0.282	1.72	n.a.	n.a.
	135.6	30	141	n.a.	n.a.	3.71	−1.24	n.a.	n.a.	3.17	4.25
	208.8	30	215	n.a.	n.a.	2.81	0.133	n.a.	n.a.	2.48	3.14
	327.5	30	337	n.a.	n.a.	2.88	0.127	n.a.	n.a.	2.62	3.14
55	36.9	30	37.8	0.933	0.233	n.a.	n.a.	0.552	1.31	n.a.	n.a.
	69.0	30	68.8	−0.233	−1.53	n.a.	n.a.	−1.06	0.594	n.a.	n.a.
	136.0	30	144	n.a.	n.a.	5.76	0.809	n.a.	n.a.	5.24	6.28
	210.2	30	216	n.a.	n.a.	2.54	−0.139	n.a.	n.a.	2.16	2.92
	322.8	30	331	n.a.	n.a.	2.57	−0.182	n.a.	n.a.	2.17	2.97
60	38.9	30	40.5	1.57	0.867	n.a.	n.a.	1.13	2.00	n.a.	n.a.
	70.4	30	70.5	0.0667	−1.23	n.a.	n.a.	−0.666	0.800	n.a.	n.a.
	137.5	30	146	n.a.	n.a.	6.28	1.33	n.a.	n.a.	5.88	6.67
	212.4	30	223	n.a.	n.a.	4.88	2.20	n.a.	n.a.	4.52	5.24
	324.3	30	332	n.a.	n.a.	2.37	−0.379	n.a.	n.a.	1.97	2.78
65	49.9	30	52.1	2.20	1.50	n.a.	n.a.	1.61	2.79	n.a.	n.a.
	69.2	30	70.1	0.867	−0.433	n.a.	n.a.	−0.0715	1.80	n.a.	n.a.
	139.2	30	147	n.a.	n.a.	5.56	0.605	n.a.	n.a.	5.05	6.06
	212.2	30	224	n.a.	n.a.	5.69	3.01	n.a.	n.a.	5.23	6.14
	324.6	30	334	n.a.	n.a.	2.97	0.215	n.a.	n.a.	2.56	3.37
70	35.3	30	36.5	1.20	0.500	n.a.	n.a.	0.582	1.82	n.a.	n.a.
	68.1	30	67.8	−0.267	−1.57	n.a.	n.a.	−1.11	0.577	n.a.	n.a.
	136.8	30	146	n.a.	n.a.	6.94	1.99	n.a.	n.a.	6.33	7.56
	210.3	30	222	n.a.	n.a.	5.53	2.86	n.a.	n.a.	4.87	6.19
	329.0	30	345	n.a.	n.a.	4.93	2.18	n.a.	n.a.	4.44	5.43

Abbreviations: BG, blood glucose; BGMS, blood glucose monitoring system; CI, confidence interval; Hct, hematocrit; n.a., not applicable.

Altitude

When compared with control, the mean absolute or relative bias did not exceed ±10 mg/dL or ±10% for any test at altitudes up to 4300 m above sea level with any of the three strip lots (Table 4).

Table 4.

Effects of Altitude.

Set	Test strip lot	Control sample mean (mg/dL)	Mean BGMS BG measurement (mg/dL)	Test sample (N)	Absolute bias (mg/dL)	Relative bias (%)	Lower CI for absolute bias (mg/dL)	Upper CI for absolute bias (mg/dL)	Lower CI for relative bias (%)	Upper CI for relative bias (%)
1	1	52.9	53	8	0.125	0.236	−0.729	0.979	−1.38	1.85
2	2	52.5	52.8	8	0.250	0.476	−1.08	1.58	−2.06	3.01
3	3	53.1	52.8	8	−0.375	−0.706	−1.85	1.10	−3.48	2.06
4	1	100	104	8	3.88	3.86	2.12	5.63	2.11	5.61
5	2	99.4	103	8	3.62	3.65	2.06	5.19	2.07	5.22
6	3	102	104	8	2.75	2.71	0.688	4.81	0.677	4.73
7	1	216	215	8	−1.38	−0.635	−4.65	1.90	−2.15	0.879
8	2	218	216	8	−2.38	−1.09	−4.77	0.0208	−2.18	0.00953
9	3	218	216	8	−1.25	−0.574	−4.36	1.86	−2.00	0.853

Abbreviations: BG, blood glucose; BGMS, blood glucose monitoring system; CI, confidence interval.

Oxygen Partial Pressure

When compared with results obtained by the plasma-based HK comparator method, all test results with all strip lots were within ±12 mg/dL or ±12% (absolute or relative) for each of the three concentration ranges tested (50-70, 110-130, and 225-270 mg/dL; Table 5).

Table 5.

Analysis of pO₂ Interference Testing Accuracy per BG Level and Test Strip Lot for All pO₂ Levels.

Test strip lot	BG target range(mg/dL)	Within 12 mg/dL / 12%	Within 15 mg/dL / 15%
1	50-70	64/64 (100%)	64/64 (100%)
	110-130	64/64 (100%)	64/64 (100%)
	225-270	64/64 (100%)	64/64 (100%)
2	50-70	64/64 (100%)	64/64 (100%)
	110-130	64/64 (100%)	64/64 (100%)
	225-270	64/64 (100%)	64/64 (100%)
3	50-70	64/64 (100%)	64/64 (100%)
	110-130	64/64 (100%)	64/64 (100%)
	225-270	64/64 (100%)	64/64 (100%)

Abbreviations: BG, blood glucose; pO₂, partial pressure of oxygen.

Flex Studies

Results for skin disinfectants met the acceptance criteria. Accuracy standards were met with proper usage of skin disinfectants. No test result was within the limits for the erroneous results zone. In cases of improper usage of the disinfectants, the failsafe was effective.

All measurements of ascorbic acid concentrations higher than 30 mg/dL were failsafe effective, and for samples with ascorbic acid concentrations of 15 and 30 mg/dL, accurate glucose readings were shown.

Correct glucose results were shown, and no failsafe was needed for hematocrit levels outside of claimed ranges.

Discussion

The BGMS assessed in the current analysis has been designed to include multiple mechanisms to reduce the potential for interference. Studies included in the comprehensive interference analysis were designed to rigorously evaluate the potential for endogenous substances and drugs, and variations in hematocrit level, oxygen partial pressure, and altitude to interfere with the performance of the BGMS. No interfering substance or condition was identified that altered the performance of the BGMS, and variations were all well inside the acceptance criteria.

In total, 29 endogenous substances and 160 drugs were evaluated in the present interference study. The results demonstrate that the BGMS is free from interference by substances that interfere with other strip-based BGMSs, such as bilirubin, galactose, and other nonglucose sugars, triglycerides, and uric acid, which are endogenous substances that have been shown to interfere with the performance of other strip-based BGMSs,^8,16,17 but not with the BGMS in this analysis. This is also true for the drugs acetaminophen, ascorbic acid, dopamine, mannitol, and icodextrin metabolites.^17-20

The potential for hematocrit level to interfere with the performance of the BGMS was thoroughly evaluated. Wide variation in hematocrit level has been shown to interfere with the performance of some strip-based BGMSs, with higher hematocrit levels being associated with lower BG values.^17,21-23 A large proportion of patients in adult intensive care units have abnormally low hematocrit levels and these values can also fluctuate daily.²⁴ Conversely, patients in neonatal intensive care units can have abnormally high hematocrit levels.²⁵ The performance of the BGMS was evaluated over a wide range of hematocrit values (5-70%) and glucose concentrations (30-400 mg/dL) without any evidence of interference.

Oxygen has the potential to interfere with the performance of BGMSs.⁸ The BGMS in this analysis is designed with oxygen-independent chemistry, eliminating per design a bias associated with changes in sample oxygen partial pressure or ambient oxygen concentration. The results of the present analysis show that the BGMS is not affected by variations in oxygen partial pressure ranging from approximately 30 to 200 mm Hg, or by elevation ranging up to approximately 4300 m above sea level.

In the flex studies, results demonstrated the BGMS’s ability to measure accurately in cases of contamination of a blood sample with skin disinfectants, high levels of ascorbic acid, or hematocrit levels outside of the claimed range.

The present study has certain limitations. All analyses involved contrived blood samples and each interfering substance or condition was evaluated in isolation. Blood samples taken from patients in health care settings may be more complex. For example, the concentration of endogenous substances may be higher or lower than that contained in our contrived samples, and patients often receive several drugs concurrently. Samples were prepared and analyzed by trained technicians in our study, whereas the instrument has been designed for use by health care professionals who may not necessarily have been trained on the proper use of the BGMS. Finally, not all potential interfering substances or environmental conditions were assessed.

Conclusions

POC performance of the BGMS in this analysis was not altered by interfering endogenous substances or drugs commonly found in the blood of hospitalized patients after a rigorous evaluation under a wide range of conditions (extreme variations in hematocrit level, partial pressure of oxygen, or altitude). Contamination of blood samples with skin disinfectants, extreme levels of ascorbic acid, or hematocrit levels outside the claimed range did not cause wrong test results.

Such a BGMS seems to be reliable and therefore of high value to patients in professional health care settings.

Supplemental Material

sj-docx-1-dst-10.1177_19322968251319344 – Supplemental material for Evaluation of Potential Interference Caused by Endogenous Substances, Drugs, and Variations of Blood Sample Properties and Environmental Conditions, With Blood Glucose Concentrations Measured With a New Strip-Based Blood Glucose Monitoring System

Supplemental material, sj-docx-1-dst-10.1177_19322968251319344 for Evaluation of Potential Interference Caused by Endogenous Substances, Drugs, and Variations of Blood Sample Properties and Environmental Conditions, With Blood Glucose Concentrations Measured With a New Strip-Based Blood Glucose Monitoring System by Michael Marquant, Simon Gessler, Michael Diechtierow, Julia Gerber and Zekiye Adar née Oeztuerk in Journal of Diabetes Science and Technology

Footnotes

Acknowledgements

Research support in the form of third-party medical writing assistance for this manuscript, furnished by Blair Jarvis, MSc, on behalf of Nucleus Global, an Inizio Company, was provided by Roche Diagnostics.

Abbreviations

BG, blood glucose; BGMS, blood glucose monitoring system; CI, confidence interval; CLSI, Clinical and Laboratory Standards Institute; EDTA, ethylenediaminetetraacetic acid; FDA, Food and Drug Administration; Hct, hematocrit; HES, hydroxyethyl starch; HK, hexokinase; LER, limits for erroneous results; n.a., not applicable; PAM, pralidoxime iodide; pO₂, partial pressure of oxygen; POC, point of care.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Michael Marquant, Simon Gessler, Michael Diechtierow, and Zekiye Adar née Oeztuerk are employees of Roche Diagnostics GmbH and hold stocks/shares in F. Hoffmann-La Roche Ltd. Julia Gerber is an employee of Roche Diagnostics International Ltd and holds stocks/shares in F. Hoffmann-La Roche Ltd. All authors received third-party writing assistance from Roche.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The development of the blood glucose monitoring system and the work described in this article was funded by Roche Diagnostics GmbH, Mannheim, Germany (no grant number applicable). The blood glucose monitoring system is approved for clinical use in Europe (CE mark-accepting countries). The blood glucose monitoring system is not yet available in the United States, but it is FDA-cleared for 510K and CLIA waived for use with arterial and heel stick whole blood samples. All product names and trademarks are the property of their respective owners.

ORCID iDs

Michael Marquant

Simon Gessler

Supplemental Material

Supplemental material for this article is available online.

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Evaluation of Potential Interference Caused by Endogenous Substances,Drugs,and Variations of Blood Sample Properties and Environmental Conditions,With Blood Glucose Concentrations Measured With a New Strip-Based Blood Glucose Monitoring System

Abstract

Background:

Methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Endogenous Substances and Drugs

Hematocrit Levels

Oxygen

Statistical Methods

Acceptance Criteria

Flex Studies

Data and Resource Availability

Results

Endogenous Substances

Drugs

Hematocrit Level

Altitude

Oxygen Partial Pressure

Flex Studies

Discussion

Conclusions

Supplemental Material

Footnotes

Acknowledgements

Abbreviations

Declaration of Conflicting Interests

Funding

ORCID iDs

Supplemental Material

References

Supplementary Material