Fixed Versus Body-Sized-Based Dosing of Monoclonal Antibodies

Abstract

Monoclonal antibody products are an increasing portion of novel drug approvals. The labeling of initial drug approvals frequently involves body-size-based rather than fixed-dose administration regimens for adults without clear rationale for doing so. This presents challenges when prescribing these products for patients with extremes of body habitus who constitute a small portion of enrollment in pre-approval investigations. Fixed-dose regimens allow for standardized preparation with the potential to reduce the risk of calculation errors, drug waste, and make home administration more practical. Fixed-dose rather than body-size-based monoclonal antibody regimens should serve as the initial approach in early phase 1 clinical trials.

As of 2021, 100 Food and Drug Administration (FDA)-approved therapeutic monoclonal antibody (mAb) were available on the market. ¹ Approximately 24% of novel drug approvals by the FDA in 2022 were for mAbs. ² Many of the initial commercially available mAbs, including the majority of mAbs with oncology-related indications, were approved with labeling based on body-size-based evaluations rather than fixed-dose administration regimens for adults without clear rationale for doing so. ³ Body-size-based evaluations were likely a legacy from traditional clinical trial development involving small molecule agents. However, body-size-based dosing regimens present challenges for clinicians prescribing mAbs for adult patients with extremes of body habitus, since the latter patients typically do not constitute a substantial portion of enrollment in investigations leading to drug approval. Body-size-based regimens also present challenges for compounding centers attempting to make advanced preparation of mAbs in batches to increase efficiency and reduce wait times for patients. Finally, body-size-based dosing regimens may lead to medication errors due to lack of information on the most appropriate choice of weight, or calculation errors especially when patients self-administer mAbs by subcutaneous (SC) injections outside of healthcare settings. The purpose of this commentary is to advocate for more fixed-dose investigations of mAbs that have proposed indications for adult patients, beginning with first-in-human studies through dose-optimization studies during phase 3 trials.

The early approval of mAbs for oncology-related indications provides the background for the current discussion of fixed- versus body-size-based dosing. In 2002, a retrospective study by Baker et al ⁴ found that of 33 anticancer medications undergoing evaluation in adult patients in phase 1 trials over a 10-year period, only 5 medications had sufficient reductions in inter-patient variability of drug clearance using body surface area (BSA)-adjusted dosing to justify a BSA dosing approach. In light of these findings, the authors proposed that future early clinical trials use a fixed-dose approach based on average BSA (at the time was 1.86 m²) with subsequent refinements in dosing based on therapeutic outcomes that include toxicity considerations.

In 2009, Wang et al. noted that of the first 18 non-radioimmunotherapeutic mAbs to receive FDA approval, 12 (67%) products had body-size-based dose labeling for adult patients. ⁵ The body-size-based dosing appeared to be a carryover from BSA-based dosing recommendations for traditional small molecule cytotoxic agents that typically had increases in volume of distribution and clearance in association with increasing body size. However, the investigators pointed out that the pharmacokinetics of mAbs are different from cytotoxic agents that are usually cleared by the kidney or liver—mAbs are distributed by convection with small volumes of distribution and eliminated by intracellular catabolism to peptides and amino acids following endocytosis. ⁶ This led the investigators to perform simulation studies evaluating fixed-versus size-based dosing regimens for 12 mAbs with published information on pharmacokinetics and pharmacodynamics (PK/PD) in adult populations. There was no clear advantage using either approach leading the investigators to recommend the fixed-dose regimen in early phase I clinical trials due to perceived advantages related to dose preparation, cost, and potential for dosing errors. The investigators stated that if data become available in later phase 1 or phase 2 trials that suggests a size-based dosing regimen might have advantages, the possibility can be evaluated by PK/PD analysis with inclusion of appropriate covariates. If no advantage is detected in phases 1 or 2 with the size-based regimen, the investigators recommended that phase 3 trials default to a fixed-dose approach. Similar findings and conclusions resulted from another much larger investigation of a company’s clinical trial database involving 2519 patients with various forms of cancer, ⁷ and a smaller investigation evaluating fixed- versus size-based approaches in non-mAb therapeutic proteins and peptides. ⁸ Coincidentally, during the same time frame when some cancer researchers were advocating for fixed-dose evaluations of oncology drugs in early clinical trials, the American Society of Clinical Oncology (ASCO) published a guideline recommending total weight-based cytotoxic chemotherapy for obese patients with cancer stating that toxicity concerns were unfounded. ⁹ The ASCO guideline did not provide recommendations for targeted agents or immunotherapy, although these therapies were considered in a 2021 ASCO guideline update. ¹⁰ Additionally, both cytotoxics and mAbs were subsequentially addressed in a consensus position paper issued by a panel of experts of the Associazione Italiana Oncologia Medica, Associazione Medici Diabetologi, Società Italiana Endocrinologia, and the Società Italiana Farmacologia (AIOM/AMD/SIE/SIF). ¹¹ These authors acknowledge important differences in the impact of obesity on pharmacokinetics and pharmacodynamics of cytotoxics and mAbs. For example, mAb binding to cell surface antigens is affected by tumor burden and receptor affinity, which is not affected by body weight. Although proteolytic catabolism of mAbs that target soluble antigens is body-weight dependent, the impact of body weight on mAb elimination is much lower due to their low clearance and volume of distribution. Since the increase in blood volume and volume of distribution associated with increasing body weight for mAbs is less significant as the increase in body weight, the lower blood volume in low body-weight patients could result in lower drug exposures, whereas the higher blood volume in obese patients could result in higher drug exposures with body-size-based dosing. ¹¹ Use of fixed-doses of mAbs would be associated with higher drug exposures in low body-weight patients with lower drug exposures expected in obese patients. ¹¹

Using a fixed-dose approach in early clinical trials of mAbs does not preclude future adjustments of dose based on new study information as exemplified by the debate of the most appropriate dosing regimen for pembrolizumab. In 2014, the FDA granted accelerated approval of pembrolizumab with a recommended dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. ¹² In 2015, the FDA granted accelerated approval of pembrolizumab at the same dose for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death ligand 1 (PD-L1) with disease progression on or after platinum-containing chemotherapy. ¹³ Using the population pharmacokinetic modeling leading to pembrolizumab approval and exposure-response data for the approved indications,^14,15 a subsequent investigation found doses of 200 mg and 2 mg/kg yield similar exposure distributions with no clear advantage with either approach for reducing pharmacokinetic variability. ¹⁶ Therefore, the 200 mg every 3 week fixed dose was subsequently incorporated into approved labeling, although there was ongoing controversy concerning the most appropriate fixed-dose regimen. ¹⁷ Some argued that based on the average weight of a cancer patient, a 150 mg dose would be more appropriate, while others raised concerns about reimbursement issues related to available vial sizes. Still others suggested a combination of dosing approaches by arguing for a 6 mg/kg dose given every 6 weeks, but with a cap of 400 mg based on more recent pharmacokinetic modeling. ¹⁸ A series of pharmacoeconomic analyses did little to quell the dosing controversy, since potential economic benefits to any given approach were shown to vary not only be country, but even at the institutional level.^19-21 Currently, 400 mg every 6 weeks is an approved dosing strategy for adults receiving pembrolizumab, a fixed-dose regimen that also is attractive for patients who have to travel long distances to an infusion center. Fixed-dose regimens are incorporated into current labeled dosing recommendations for most immune checkpoint inhibitors. ²²

As demonstrated by the pembrolizumab example, 1 fixed-dose regimen may not be appropriate for all adult patients based on efficacy, safety, or cost-effectiveness concerns. However, it may be possible to limit the number of fixed doses, while considering the influence of patient weight on mAb pharmacokinetics. For example, dose response studies (using 10 kg weight increments) evaluating the efficacy and serum ustekinumab concentrations of ustekinumab in patients with psoriasis and psoriatic arthritis found that median trough concentrations and efficacy of the mAb were similar when patients less than 100 kg were given a 45 mg dose and patients more than 100 kg were given a 90 mg dose, so the labeling for SC administration reflects these findings.^23,24 The study investigators did note the relatively low numbers of patients evaluated at extremes of body weight (>130 kg), thereby limiting definitive conclusions about the most appropriate dose. However, similar findings were observed with secukinumab, where investigators noted that obesity is associated with lower mean serum secukinumab concentrations. ²⁵ Heavier patients with moderate-to-severe plaque psoriasis (≥90 kg) benefit from a 300 mg every 2-week dosing regimen compared to the same dose administered every 4 weeks, ²⁵ but this information is not reflected in the label. ²⁶

Antibody-drug conjugates (ADCs), a rapidly growing class of anticancer drugs, may also be appropriate for fixed-doses, although the labeled doses for all 11 current FDA-approved ADCs are based on body weight or BSA with some products having maximum doses (e.g., brentuximab vedotin, tisotumab vedotin, enfortumab vedotin). Mirvetuximab soravtansine, a folate receptor α-targeted ADC that just came on the market, has dosing based on adjusted body weight (with the usual 0.4 correction factor for the excess weight). Early analyses performed during the phase 1 dose-escalation study identified dose-dependent and exposure-dependent ocular adverse events. ²⁷ The initial dose calculations based on total body weight were subsequently modified to reduce interpatient variability in drug exposure and to decrease the incidence of ocular adverse events. Antibody-drug conjugates are composed of an antigen-specific mAb, a potent cytotoxic agent, and a stable linker that releases the conjugated cytotoxic payload into the tumor. Their therapeutic indices are narrower than those of non-ADC mAbs. ²⁸ Optimal dosing strategies must consider differences between the pharmacokinetics and pharmacokinetics of the mAb and the cytotoxic, with recognition that the cytotoxic payload toxicities are dose-limiting.^11,29 In a retrospective study of 44 obese and 75 non-obese patients receiving ado-trastuzumab emtansine (dose based on total body weight) for breast cancer, the incidence of treatment modifications, delays, and adverse events was higher in obese patients, ³⁰ suggesting that dosing based on total body weight may lead to excess drug exposures in obese patients. Of note, overweight and obesity are risk factors for cardiotoxicity with both trastuzumab and anthracyclines. ³¹ These observations regarding adverse events are consistent with projections for elevated drug exposures in this patient population. ¹¹

The need for evaluation of fixed-dose regimens in early clinical trials is exacerbated by the increasing number of mAbs available for SC administration by patients outside hospital settings, since SC delivery as an alternative to intravenous infusions is effective, safe, patient-centered, and often associated with decreased healthcare costs. ³² Examples of current agents amenable to SC administration in home settings include rheumatologic agents such as anti-TNFα, anti-IL-1, anti-IL-6 and emicizumab-kxwh for hemophilia A. Although injectable oncology medications are currently only approved for administration in healthcare settings, an increasing number are available in SC dosing forms including trastuzumab/hyaluronidase-oysk, daratumumab/hyaluronidase-fihj, pertuzumab/trastuzumab/hyaluronidase-zzxf, rituximab/hyaluronidase, and teclistamab-cqyv.

The SQ trastuzumab/hyaluronidase-oysk flat-dose regimen is considered non-inferior to the weight-based trastuzumab regimen, although a comparison of trastuzumab exposures in patients with a body mass index (BMI) ≥30 showed that the proportion of patients that achieved a historical target plasma concentration of 20 ug/mL after initial dosing was significantly higher when trastuzumab was administered intravenously. ³³ A scoping review confirmed that risk of below-target trastuzumab exposure was greater in overweight/obese patients, but low body-weight patients were not at increased risk for trastuzumab toxicity with the SC trastuzumab compared to intravenous dosing. ³⁴ The fixed-dose pertuzumab/trastuzumab/hyaluronidase-zzxf combination SQ injection was also non-inferior to IV administration for serum trough concentrations, efficacy, and safety profiles. Heavier patients had lower serum pertuzumab exposures due to lower drug clearance in patients with increased lean body weight. ³⁵ Dose-optimization strategies for obese patients that employ fixed doses might be feasible using shorter dosing intervals, similar to observations using an approach investigated with secukinumab. ²⁵ Depending on the pharmacokinetic or pharmacodynamic behavior of the mAb, loading doses may be appropriate. ³⁶

Some mAb products have formulations for both SC and IV administration, which raises issues related to payer coverage, patient preferences, adverse effects, and preparation (e.g., usual patient dose different than the dose of the container) and stability issues. A full discussion of these topics is beyond the scope of this paper. However, daratumumab serves as a useful example of adverse effects related to route of administration. Daratumumab has complicated recommendations for rate titration with the formulation given by weight-based IV infusion. ³⁷ This can lead to medication administration errors not associated with fixed-dose SC dosing.

Fixed-dose medication regimens have several potential advantages over body-size-based regimens, including convenience, reduced wastage, and cost especially for products (e.g., without preservatives) that cannot be used for more than 1 patient, and reductions in dosing calculation errors. As mAbs account for an increasing amount of novel drug approvals by the FDA, fixed-dose rather than body-size-based regimens should serve as the initial approach in early phase 1 clinical trials, particularly for those mAbs administered by SC injection that are likely to be administered outside of hospital settings. Additionally, investigators conducting pre-approval studies should strive to include patients of more extreme body habitus to help determine the most appropriate dosing regimen.