Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects.
Methods:
We assessed the effect of mometasone delivered directly to the lung in two different rodent PD models of lung inflammation. The data obtained were used to develop and evaluate a mathematical model to estimate drug dissolution, transport, distribution, and efficacy, following inhaled delivery in rodents and humans.
Results:
Mometasone directly delivered to the lung, in both LPS and Alternaria alternata rat models, resulted in dose dependent inhibition of BALf cellular inflammation. The parameters for our mathematical model were calibrated to describe the observed lung and systemic exposure profiles of mometasone in humans and in animal models. We found that physicochemical properties, such as lung fluid solubility and lipophilicity, strongly influenced compound distribution and lung retention.
Conclusions:
Presently, we report on a novel and sophisticated mathematical model leading to improvements in a current inhaled drug development practices by providing a quantitative understanding of the relationship between PD effects and drug concentration in lungs.
Get full access to this article
View all access options for this article.
References
1.
BousquetJ, and KhaltaevN, eds: Global Surveillance, Prevention and Control of Chronic Respiratory Diseases: A Comprehensive Approach. World Health Organization. 2007.
2.
Diaz-GuzmanE, and ManninoDM: Epidemiology and prevalence of chronic obstructive pulmonary disease. Clin Chest Med. 2014; 35:7–16.
3.
MullaneK: The increasing challenge of discovering asthma drugs. Biochem Pharmacol. 2011; 82:586–599.
4.
CooperAE, FergusonD, and GrimeK: Optimisation of DMPK by the inhaled route: Challenges and approaches. Curr Drug Metab. 2012; 13:457–473.
5.
KleinNC, GoCH, and CunhaBA: Infections associated with steroid use. Infect Dis Clin North Am. 2001; 15:423–432.
6.
ToogoodJH: Efficiency of inhaled versus oral steroid treatment of chronic asthma. N Engl Reg Allergy Proc. 1987; 8:98–103.
7.
LipworthBJ, and JacksonCM: Effects of oral and inhaled corticosteroids on the hypothalamic-pituitary-adrenal axis. J Allergy Clin Immunol. 1999; 104:713–714.
8.
DahlR, ChuchalinA, GorD, YoxallS, and SharmaR: EXCEL: A randomised trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma. Respir Med. 2006; 100:1152–1162.
9.
FramptonJE: Mometasone/formoterol inhalation aerosol: In asthma uncontrolled on medium- or high-dose inhaled corticosteroids. Drugs. 2012; 72:1229–1241.
10.
ForbesB, AsgharianB, DaileyLA, FergusonD, GerdeP, GumbletonM, GustavssonL, HardyC, HassallD, JonesR, LockR, MaasJ, McGovernT, PitcairnGR, SomersG, and WolffRK: Challenges in inhaled product development and opportunities for open innovation. Adv Drug Deliv Rev. 2011; 63:69–87.
11.
ChengYS: Mechanisms of pharmaceutical aerosol deposition in the respiratory tract. AAPS Pharm Sci Tech. 2014; 15:630–640.
12.
WeberB, and HochhausG: A pharmacokinetic simulation tool for inhaled corticosteroids. AAPS J. 2013; 15:159–171.
13.
YuJ, and RosaniaGR: Cell-based multiscale computational modeling of small molecule absorption and retention in the lungs. Pharmaceut Res. 2010; 27:457–467.
14.
YuJ, ZhengN, ManeG, KyoungAM, HinestrozaJP, ZhuH, StringerKA, and RosaniaGR: A cell-based computational modeling approach for developing site-directed molecular probes, PLoS Comput Biol., 2012; 8:e1002378.
15.
MortimerKJ, HarrisonTW, TangY, WuK, LewisS, SahasranamanS, HochhausG, and TattersfieldAE: Plasma concentrations of inhaled corticosteroids in relation to airflow obstruction in asthma. Br J Clin Pharmacol. 2006; 62:412–419.
16.
GilMA, CanigaM, WoodhouseJD, EckmanJ, LeeH-H, SalmonM, NaberJ, HamiltonVT, SevillaRS, BettanoK, KlappenbachJ, MoyL, CorrellCC, GervaisFG, SiliphaivanhP, ZhangW, Zhang-HooverJ, McLeodRL, and CicmilM: Anti-inflammatory actions of CRTH2 and glucocorticoid receptor antagonism in a novel rat model of Alternaria alternata elicited pulmonary inflammation. Eur J Pharmacol. 2014; 743C:106–116.
17.
AlexanderDJ, CollinsCJ, CoombsDW, GilkisonIS, HardyCJ, HealeyG, KarantabiasG, JohnsonN, KarlssonA, KilgourJD, and McDonaldP: Association of Inhalation Toxicologists (AIT) working party recommendation for standard delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals. Inhal Toxicol. 2008; 20:1179–1189.
18.
BergerR, and BergerWE: Particle size and small airway effects of mometasone furoate delivered by dry powder inhaler. Allergy Asthma Proc. 2013; 34:52–58.
19.
HintzRJ, and JohnsonCS: The effect of particle size distribution on dissolution rate and oral absorption. Int J Pharmaceut. 1989; 51:9–17.
20.
NoyesAA, and WhitneyWR: The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897; 19:930–934.
21.
HochhausG: Pharmacokinetic/pharmacodynamic profile of mometasone furoate nasal spray: Potential effects on clinical safety and efficacy. Clin Ther. 2008; 30:1–13.
22.
DaviesB, and MorrisT: Physiological parameters in laboratory animals and humans. Pharm Res. 1993; 10:1093–1095.
23.
AffrimeMB, CussF, PadhiD, WirthM, PaiS, ClementRP, LimJ, KantesariaB, AltonK, and CayenMN: Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers. J Clin Pharmacol. 2000; 40:1227–1236.
24.
ScheuchG, KohlhaeuflMJ, BrandP, and SiekmeierR: Clinical perspectives on pulmonary systemic and macromolecular delivery. Adv Drug Deliv Rev. 2006; 58:996–1008.
25.
BartonBE, JakwayJP, SmithSR, and SiegelMI: Cytokine inhibition by a novel steroid, mometasone furoate. Immunopharmacol Immunotoxicol. 1991; 13:251–261.
26.
DerendorfH, NaveR, DrollmannA, CerasoliF, and WurstW: Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eur Respir J. 2006; 28:1042–1050.
27.
NathanRA, NayakAS, GraftDF, LawrenceM, PiconeFJ, AhmedT, WolfeJ, VanderwalkerML, NolopKB, and HarrisonJE: Mometasone furoate: Efficacy and safety in moderate asthma compared with beclomethasone dipropionate. Ann Allergy Asthma Immunol. 2001; 86:203–210.
28.
NayakAS, BanovC, CorrenJ, FeinsteinBK, FloreaniA, FriedmanBF, GoldsobelA, GottschlichGM, HannawayPJ, LamplKL, LapidusRJ, LawrenceM, LumryW, MunkZ, PearlmanD, ScardellaAT, SchenkelEJ, SegalAT, SegallN, SilvermanB, ShneyerL, NolopKB, and HarrisonJE: Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma. Ann Allergy Asthma Immunol. 2000; 84:417–424.
29.
NoonanM, KarpelJP, BenschGW, RamsdellJW, WebbDR, and NolopKB, LutskyBN: Comparison of once-daily to twice-daily treatment with mometasone furoate dry powder inhaler. Ann Allergy Asthma Immunol. 2001; 86:36–43.
30.
ChapmanRW, CurranAK, HouseA, RichardJ, SalisburyB, HunterJC, AnthesJC, and PhillipsJE: Effect of mometasone furoate (MF)/formoterol fumarate (F) combination (MF/F) on late-phase responses in allergen-challenged Brown Norway rats. Pulm Pharmacol Ther. 2011; 24:67–73.
31.
van HeldenHP, KuijpersWC, SteenvoordenD, GoC, BruijnzeelPL, van EijkM, and HaagsmanHP: Intratracheal aerosolization of endotoxin (LPS) in the rat: A comprehensive animal model to study adult (acute) respiratory distress syndrome. Exp Lung Res. 1997; 23:297–316.
32.
DohertyTA, KhorramN, SugimotoK, SheppardD, RosenthalP, ChoJY, PhamA, MillerM, CroftM, and BroideDH: Alternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness. J Immunol. 2012; 188:2622–2629.
33.
DohertyTA, KhorramN, ChangJE, KimHK, RosenthalP, CroftM, and BroideDH: STAT6 regulates natural helper cell proliferation during lung inflammation initiated by Alternaria. Am J Physiol Lung Cell Mol Physiol. 2012; 303:L577–588.
34.
BartemesKR, IijimaK, KobayashiT, KephartGM, McKenzieAN, and KitaH: IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol. 2012; 188:1503–1513.
35.
JanssonAH, ErikssonC, and WangX: Effects of budesonide and N-acetylcysteine on acute lung hyperinflation, inflammation and injury in rats. Vascul Pharmacol. 2005; 43:101–111.
36.
NialsAT, Tralau-StewartCJ, GascoigneMH, BallDI, and RanshawLE, KnowlesRG: In vivo characterization of GSK256066, a high-affinity inhaled phosphodiesterase 4 inhibitor. J Pharmacol Exp Ther. 2011; 337:137–144.
37.
OlssonB, BondessonE, BorgströmL, EdsbäckerS, EirefeltS, EkelundK, GustavssonL, and Heglund-MyrbäkT: Pulmonary drug metabolism, clearance, and absorption. In: SmythHDC, HickeyAJ, (eds.) Controlled Pulmonary Drug Delivery. Springer, New York; 2–11; pp. 21–50.
38.
WuK, BlomgrenAL, EkholmK, WeberB, EdsbaeckerS, and HochhausG: Budesonide and ciclesonide: Effect of tissue binding on pulmonary receptor binding. Drug Metab Dispos. 2009; 37:1421–1426.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
