Use of modeling and simulation methods to support the generic application of a vaginal delivery system
Esther Encinas (1), John C. Lukas (1), Paula Muñiz (1), Monica Rodriguez (1), Nerea Leal (1), Sigrun Hrafnsdottir (2), Gerald Beuerle (3)
(1) Drug Modeling & Consulting, Dynakin S.L., Bilbao, Spain; (2) Actavis, Hafnarfjordur, Iceland; (3) Teva ratiopharm GmbH, Ulm, Germany
Introduction: A pharmaceutical company developed a generic contraceptive vaginal delivery system containing etonogestrel (ENG, 0.120 mg/day) and ethinyl estradiol (EE, 0.015 mg/day), equivalent according to in vitro criteria and bioequivalent in vivo to the Reference (R) NuvaRing®. A 2x2 crossover bioequivalence study was conducted in 48 females under the recommended 21-day use [1], but health authorities were concerned about its appropriateness to support the extended 28-day use for the test (T) ring, a deviation already allowed for NuvaRing [1].
Objectives: To develop an in vitro-in vivo correlation (IVIVC) model, based on in vivo 21-day PK data and 28-day in vitro release profiles of ENG and EE from both T and R vaginal rings, aimed to support that enough serum levels of EE/ENG are achieved during the additional 4th week of use. The ultimate purpose was to evaluate the representativeness of in vitro release rate to in vivo behaviour for two bioequivalent products but prolonged in time, once in equilibrium.
Methods: A direct (one step) differential equation-based IVIVC model (an alternative method to classical two-step level A IVIVC approach [2]) was developed and was able to predict, within a traditional compartmental model framework [3], the entire in vivo plasma PK profile based on in vitro release rates (N=12 replicates in discriminative medium), separately for ENG and EE components. The approach requires first model parameterization of the in vitro dissolution rates that can then be integrated into an input driving a compartmental PK structure for the in vivo behaviour.
In vivo concentrations were modeled via inclusion of both the (separately developed) in vitro dissolution rate model structure, transformed by scaling into the in vivo release rate, and the in vivo PK simultaneously. NuvaRing data were used in model development; the in vitro parameters introduced in the global in vitro/in vivo structure were fixed to those estimated in in vitro modeling and appropriate time-scales were estimated as fixed effects together with systemic PK. The bioavailability was modeled with a time-dependent function, consistent with reports for both ENG [4] and EE [5]. An impulse function represented 21- or 28-day removal of the ring.
When predicting in vivo profiles from the generic ring, the previously estimated in vivo parameters were then fixed, while the in vitro parameter set was switched with that of T to drive the simulation. Once externally qualified through prediction errors (PE) and visual predictive check (VPC) against PK observations for T, the direct IVIVC model was used in extrapolating in time by prolonging exposure to the input rate from 21 to 28 days. Predictability was confirmed by comparison with literature 28-day PK data for NuvaRing. All modeling was conducted in NONMEM v7.3 (FOCE method) and graphics were performed using S-PLUS v8.
Results: A novel bi-exponential decay function best described in vitro dissolution rates for both ENG and EE. The direct IVIVC for vaginal ring compounds comprised a two-compartment disposition model with a total of 13 parameters, including an impulse function to represent removal of the ring at either 21 or 28 days and a time scale to transform in vitro to in vivo. Proportional error was assumed for the random effects. All the direct IVIVC population parameters for EE and ENG were well estimated using R data (SEE<30%), whereas external validation was confirmed by adequate prediction of in vivo 21-day PK for T (PE<5% for exposure and plasma concentration at Day 21, AUC0-21 and C21, for both analytes). When extrapolating to Day 28, PE against literature observations for NuvaRing [6] was <10% for AUC0-28 and C28, thus proving that in vitro release rate adequately represents in vivo behaviour of vaginal delivery systems and that the model is suitable for prediction of extended use. Plasma levels of ENG and EE predicted at Day 28 were similar for T and R, and well above the efficacy thresholds (e.g., 90 pg/ml for ENG [7,8]). T/R ratios predicted for both AUC0-28 and C28 of ENG were 0.95, while they were 0.92 and 0.94, respectively, for EE.
Conclusions: Direct IVIVC modeling & simulation supported the appropriateness of the generic vaginal delivery system for 28-day lengthened use by showing that sufficient serum levels of ENG and EE are maintained for an additional 4th week, thus evidencing a negligible risk of bioinequivalence at 28 days.
References:
[1] NuvaRing® etonogestrel/ethinyl estradiol 0.120 mg/0.015 mg per 24 hours, vaginal delivery system. Summary of product characteristics
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