Razvoj pristopa za vrednotenje bioekvivalence z integriranim farmakokinetičnim modelom

Dvoršič, Mojca (author), Grabnar, Iztok (mentor)

Populacijska farmakokinetika je analiza farmakokinetike na ravni populacije, pri kateri se podatki vseh posameznikov v populaciji sočasno ovrednotijo, najpogosteje z uporabo nelinearnega modela mešanih učinkov. Ker pristop preučuje celotno populacijo in ne vsakega bolnika posebej, omogoča večjo prilagodljivost tako pri številu vzorcev kot tudi pri času odvzema vzorcev. Standardna metoda ocene bioekvivalence zahteva strog režim vzorčenja za pridobitev popolnih individualnih časovno-koncentracijskih profilov, kar pa ni vedno izvedljivo. Namen našega dela je bilo razviti pristop za vrednotenje bioekvivalence z integriranim populacijskim farmakokinetičnim modelom in pristop primerjati s standardno in uveljavljeno metodo ocene bioekvivalence. Za klinično študijo s 16 prostovoljci smo s standardno metodo ocenili bioekvivalenco zdravila efavirenz. Z neprostorsko analizo smo izračunali razmerje med testno in referenčno formulacijo in 90-odstotni interval zaupanja za farmakokinetične parametre Cmax, AUCt in AUCinf. Spodnja meja 90-odstotnega intervala zaupanja parametra Cmax je bila izven sprejemljivega območja 80 % -125 %, zato bioekvivalence nismo dokazali. Na podlagi iste klinične študije smo razvili štiri populacijske farmakokinetične modele. Modele smo ovrednotili in izbrali najustreznejšega za opis naših podatkov. Izbrali smo dvoprostorni model s prvim redom absorpcije. Po metodi ponovnega vzorčenja pomembnosti smo pridobili vrednosti farmakokinetičnih parametrov, ki opisujejo model in njihovo negotovost. Iz normalne porazdelitve smo naključno vzorčili 1000 nizov parametrov in jih uporabili za simulacijo 1000 bioekvivalenčnih študij. Za vseh 1000 študij smo z neprostorsko analizo izračunali razmerje med testno in referenčno formulacijo za farmakokinetične parametre Cmax, AUCt in AUCinf. Iz razmerij smo izračunali povprečje in 90-odstotni interval zaupanja. Za vse parametre so bili intervali znotraj sprejemljivega območja in lahko zaključimo, da sta formulaciji bioekvivalentni. Iz razlik pri oceni bioekvivalence po obeh metodah lahko zaključimo, da razvit populacijski farmakokinetični model slabo opiše fazo absorpcije in maksimalno koncentracijo.

• Language: Slovenian
• Keywords: bioekvivalenca, klinična študija, NONMEM, populacijski farmakokinetični model
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-143469
• Publication date in RUL: 22.12.2022

Secondary language

• Language: English
• Title: Development of integrated pharmacokinetic model based bioequivalence assessment

Abstract

Population pharmacokinetics is the study of pharmacokinetics at the population level in which data from all individuals in a population are evaluated simultaneously, most commonly using a non-linear mixed-effects model. Because it approaches the population as a whole rather than each patient individually, it allows for greater flexibility in the number of samples and the timing of sample collection. The standard bioequivalence assessment method requires a rigorous sampling regime to obtain complete individual time-concentration profiles, which is not always feasible. Our work aimed to develop an approach for bioequivalence assessment using an integrated population pharmacokinetic model and to compare it with a standard and established bioequivalence assessment method. Bioequivalence was assessed using the standard method for a clinical study with efavirenz in 16 volunteers. A non-compartmental analysis was used to calculate the test ratio to reference formulation and 90% confidence intervals for the pharmacokinetic parameters Cmax, AUCt, and AUCinf. The lower interval limit of the Cmax parameter was outside of the acceptable range of 80% - 125%. Therefore bioequivalence was not demonstrated. Four population pharmacokinetic models were developed based on the same clinical study. We evaluated the models and selected the most suitable one to describe our data. We chose a two-compartment model with first-order absorption. The values of the pharmacokinetic parameters describing the model and their uncertainty were obtained by sampling importance resampling. We randomly sampled 1000 parameter sets from a normal distribution and used them to simulate 1000 bioequivalence studies. For all 1000 studies, we calculated the ratio between the test and reference formulation for the pharmacokinetic parameters Cmax, AUCt, and AUCinf by non-compartmental analysis. From the ratios, the mean and the 90% confidence interval were calculated. For all parameters, the intervals were within the acceptable range, and it can be concluded that the two formulations are bioequivalent. The differences in the bioequivalence assessments show that the developed population pharmacokinetic model poorly describes the absorption phase and the maximum concentration.

• Keywords: bioequivalence, clinical study, NONMEM, population pharmacokinetic model