Application of statistical approaches in the assessment of rate and extent of absorption and development of a population pharmacokinetic model for clopidogrel and its metabolite clopidogrel carboxylic acid from generic products

Abstract

Klopidogrel je inhibitor agregacije trombocita, prolek koji se posle p.o. primene brzo resorbuje i intenzivno metaboliše, pre svega presistemski u jetri, pri čemu se veći deo primenjene doze konvertuje do neaktivnog metabolita klopidogrel karboksilne kiseline, a manji deo, oko 15%, do aktivnog metabolita klopidogrel tiola, preko koga klopidogrel ostvaruje svoj efekat. Na tržištu je prisutno više generičkih lekova, za koje je potvrđena biološka ekvivalentnost sa istim referentnim lekom, dok između samih generičkih lekova nije direktno potvrđena. Budući da klopidogrel ima varijabilnu farmakokinetiku, kao i odgovor na terapiju ovim lekom, za kliničku praksu mogu biti značajne informacije o eventualnim razlikama između generičkih lekova u brzini i stepenu resorpcije, zbog kojih kod pacijenata potencijalno može da se poveća rizik od pojave neželjenih reakcija. Cilj prvog dela disertacije bio je poređenje brzine i stepena resorpcije između 19 generičkih lekova klopidogrela, metodama indirektnog i direktnog poređenja, pri čemu su korišćeni rezultati studija biološke ekvivalentnosti koji uključuju primarne i/ili sekundarne podatke za klopidogrel i klopidogrel karboksilnu kiselinu. Cilj drugog dela istraživanja bio je karakterizacija procesa resorpcije i dispozicije klopidogrela, kao i njegove konverzije do klopidogrel karboksilne kiseline, kroz razvoj i validaciju združenog populacionog farmakokinetičkog modela, uz razmatranje faktora varijabilnosti, korišćenjem koncentracija klopidogrela i klopidogrel karboksilne kiseline i drugih dostupnih relevantnih primarnih podataka iz dve studije biološke ekvivalentnosti. Metodom prilagođenog indirektnog poređenja obrađeni su podaci za klopidogrel i klopidogrel karboksilnu kiselinu iz 19 studija biološke ekvivalentnosti i utvrđene su kombinacije generičkih lekova klopidogrela koje se mogu smatrati međusobno biološki ekvivalentnim i potencijalno zamenjivim u kliničkoj praksi (76%), kao i one za koje se zamena ne preporučuje. Direktnim poređenjem farmakokinetičkih parametara iz dve studije biološke ekvivalentnosti korišćenjem Student t-testa, utvrđena je sličnost između generičkih lekova ispitivanih u ovim studijama u pogledu stepena resorpcije kopidogrela i njegove konverzije do klopidogrel karboksilne kiseline, ali ne i u pogledu brzine ovih procesa. Budući da je klinički značaj stepena resorpcije veći u odnosu na brzinu ovog procesa, može se smatrati da između ova dva generička leka nema statistički značajne razlike u biološkoj raspoloživosti. Metodom nelinearnog modelovanja kombinovaniah efekata razvijen je i validiran združeni semi-fiziološki populacioni farmakokinetički model kopidogrela i klopidogrel karboksilne kiseline, koji uključuje linearnu resorpciju sa 2 tranzitna prostora, hepatički prostor za opisivanje presistemskog metabolizma do metabolita, jednoprostorni model za klopidogrel, dvoprostorni model za klopidogrel karboksilnu kiselinu, linearnu eliminaciju ovog metbolita, alomerijsko skaliranje klirensa i volumena distribucije. Razvijeni model daje čvrstu osnovu za potencijalna buduća poboljšanja pri građenju složenijeg modela. Sprovedeno istraživanje koristi savremene metode analize sekundarnih i/ili primarnih podataka dostupnih za generičke lekove klopidogrela i pruža dodatne informacije o međusobnoj zamenjivosti lekova, koje mogu biti od koristi u kliničkoj praksi, te predstavlja iskorak u pravcu primene alternativnih metoda u svrhu poređenja biološke raspoloživosti lekova kod kojih nije pogodan standardni pristup predviđen aktuelnom regulativom.Clopidogrel, a platelet aggregation inhibitor, is a prodrug that undergoes rapid absorption and extensive hepatic first-pass metabolism after p.o. administration. The majority of the dose is metabolized into the inactive metabolite clopidogrel carboxylic acid, while only about 15% is converted into the active metabolite clopidogrel thiol, responsible for the clopidogrel therapeutic effect. Given its variable pharmacokinetics and therapeutic response, understanding differences in the rate and extent of absorption between generic products is crucial, as these differences could potentially impact patient safety or therapeutic outcomes. Although generic products are individually bioequivalent to the reference drug, bioequivalence between generics has not been directly assessed. The dissertation aimed to address this gap through two main objectives. In the first part of the dissertation the aim was to compare the rate and extent of absorption between 19 generic clopidogrel drugs, using indirect and direct comparison methods, analyzing primary and/or secondary data for clopidogrel and clopidogrel carboxylic acid originated from the bioequivalence studies. The aim of the second part of the research was to characterize the process of absorption and disposition of clopidogrel, as well as its conversion to clopidogrel carboxylic acid, through the development and validation of a joint population pharmacokinetic model, considering also variability factors. Clopidogrel and clopidogrel carboxylic acid concentrations as well as other available relevant primary data from two bioequivalence studies were used for model development. Data for clopidogrel and clopidogrel carboxylic acid from 19 bioequivalence studies were analyzed using adjusted indirect comparison method, which allowed the identification of combinations of generic clopidogrel drugs that can be considered mutually bioequivalent and potentially interchangeable in clinical practice (76%), as well as those for which substitution is not recommended. A direct comparison of pharmacokinetic parameters from two bioequivalence studies using Student t-test showed similarity between the generic drugs from these studies in the extent of clopidogrel absorption and its conversion to clopidogrel carboxylic acid, but not in terms of the rate of these processes. Since the extent of absorption is clinically more important compared to the rate of this process, these differences were deemed not statistically significant. A joint semi-physiological population pharmacokinetic model for clopidogrel and clopidogrel carboxylic acid was developed and validated using the nonlinear mixed effects modeling approach. Model included linear absorption with 2 transit compartments, hepatic compartment for describing clopidogrel presystemic metabolism to metabolites, one-compartment model for clopidogrel, two-compartment model for clopidogrel carboxyl acid, linear elimination of this metabolite, allomeric scaling of clearance and volume of distribution. The developed model provides a solid base for potential future improvements in building a more complex model. This research uses state-of-the-art methods for analyzing secondary and/or primary data available for generic clopidogrel drugs and provides additional information on interchangeability of these drugs, especially for cases where traditional regulatory approaches may not suffice. It provides additional data that can inform clinical decision-making and optimize the use of generic clopidogrel products in practice