Joanneke Overbeek (1), Angela Colbers (1), David Burger (1), Nielka van Erp (1), Rob ter Heine (1)
(1) Department of Pharmacy, Radboudumc Research Institute for Medical Innovation, Nijmegen, the Netherlands
Objectives: Cobicistat (COBI) is a selective, mechanism-based inhibitor of the cytochrome P450 (CYP) 3A-enzyme.(1) COBI is approved for pharmacokinetic (PK) boosting of antiretroviral drugs metabolized by CYP3A. Inhibition of CYP3A increases the systemic exposure of CYP3A-substrates by increasing bioavailability and reducing clearance. In clinical practice, COBI facilitates lower or less frequent dosing of CYP3A-substrates. PK boosting is gaining interest in populations other than HIV to reduce financial toxicity of expensive therapies.(2-4) PK of COBI, a substrate of CYP3A and CYP2D6, could be altered in different patient populations, due to differences in disposition, interaction potential of comedication, and used dose. We aimed to describe the PK of once and twice daily COBI regimens in various patient groups, including rheumatoid arthritis (RA), cancer and HIV-infection.
Methods:
PK data from four clinical trials, which were previously published elsewhere, were used.(3, 5-7) COBI was administered orally at a dose of 150 mg once daily in healthy subjects, patients living with HIV or RA, and at a dose of 150 mg twice daily in patients with cancer. In HIV-patients, COBI was combined with elvitegravir, emtricitabine and tenofovir disoproxil fumarate/tenofovir alafenamide, or with daclatasvir and the potent CYP3A-inhibitor atazanavir in healthy subjects. In patients with RA, COBI was combined with tofacitinib and in patients with cancer with the weak CYP3A-inhibitor olaparib. All plasma samples were analysed using a validated LC-MS/MS assay with a range of detection from 0.03 to 6 mg/L.
Population PK analysis was performed by means of non-linear mixed effects modelling (NONMEM V7.51). Initially, a conventional compartmental model was used to describe COBI PK. Several approaches (e.g. transit compartments, lag time) were applied to describe oral absorption. The inter-individual variability was assumed to be log-normally distributed. Sequentially, a mechanistic well-stirred liver model (WSLM) was evaluated for their ability to describe COBI PK. Allometric scaling based on total body weight was applied to the absorption rate constant and volume of distribution. Intrinsic clearance of COBI was indirectly scaled by scaling of the predicted liver volume. The concurrent use of atazanavir, tofacitinib and olaparib were evaluated as covariates on both bioavailability and apparent oral clearance. Inclusion of a covariate in the final model was based on physiological plausibility of the estimated effect and statistical significance (p<0.05, dOFV< -3.84).
Results:
In total, 684 plasma concentrations from 66 subjects were included in the analysis. PK was best described with one central compartment with Erlang type absorption (n=3 transit compartments) for the oral absorption. A combined proportional and additive error model was used to describe the residual error. The WSLM performed similar as the conventional compartmental model (AIC -1369 vs -1308 for the WSLM vs conventional model). The WSLM was selected with the lowest AIC and as the most physiologically plausible.
Olaparib increased COBI intrinsic clearance by 21% (dOFV –11.246, p<0.05). This covariate was not included in the final model, as there was no physiologically plausible explanation. Possible inhibition of intrinsic clearance was expected, due to auto-inhibition of COBI at twice-daily dosing regimens. The induction of the intrinsic clearance was attributed to the selection bias of the study population of the clinical trial, where only cancer patients who tolerated olaparib well were included. As olaparib toxicity is related to exposure, only patients with low exposure might have been included. Since this could be a study-specific finding, this covariate was not included in the final model to improve external validity. The final model population PK estimates were Ktr 4.09 h-1 (RSE 10%), Vc 71.7 L (RSE 7%), CLint 333 L.h-1.Lliver-1 (RSE 6.5%). The inter-individual variability on Ktr, Vc and CLint were 0.381 (RSE 20.4%), 0.174 (RSE 19.3%) and 0.213 (RSE 22.2%), respectively. The proportional and additive residual error were 0.0301 (RSE 6.2%) and 0.0011 (26.5%), respectively.
Conclusions: This pooled analysis of four clinical trials shows that COBI PK was well-described by a WSLM. Given the rapidly growing interest in COBI as a booster in broader populations, this model provides a tool to evaluate co COBI PK and explore alternative dosing regimens to boost other drugs.
References:
[1] Xu L, Liu H, Murray BP, Callebaut C, Lee MS, Hong A, et al. Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer. ACS Med Chem Lett. 2010;1(5):209-13.
[2] Eisenmann ED, Talebi Z, Sparreboom A, Baker SD. Boosting the oral bioavailability of anticancer drugs through intentional drug-drug interactions. Basic Clin Pharmacol Toxicol. 2022;130 Suppl 1(Suppl 1):23-35.
[3] van der Togt CJT, Verhoef LM, van den Bemt BJF, den Broeder N, Ter Heine R, den Broeder AA. Pharmacokinetic boosting to enable a once-daily reduced dose of tofacitinib in patients with rheumatoid arthritis and psoriatic arthritis (the PRACTICAL study). Ther Adv Musculoskelet Dis. 2022;14:1759720×221142277.
[4] Boffito M, Back D, Gatell JM. Twenty years of boosting antiretroviral agents: where are we today? Aids. 2015;29(17):2229-33.
[5] Overbeek JK, Guchelaar NAD, Mohmaed Ali MI, Ottevanger PB, Bloemendal HJ, Koolen SLW, et al. Pharmacokinetic boosting of olaparib: A randomised, cross-over study (PROACTIVE-study). Eur J Cancer. 2023;194:113346.
[6] Bukkems V, Necsoi C, Tenorio CH, Garcia C, Rockstroh J, Schwarze-Zander C, et al. Clinically Significant Lower Elvitegravir Exposure During the Third Trimester of Pregnant Patients Living With Human Immunodeficiency Virus: Data From the Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) Network. Clin Infect Dis. 2020;71(10):e714-e7.
[7] Smolders EJ, Colbers EP, de Kanter CT, Velthoven-Graafland K, Drenth JP, Burger DM. Daclatasvir 30 mg/day is the correct dose for patients taking atazanavir/cobicistat. J Antimicrob Chemother. 2017;72(2):486-9.
Reference: PAGE 32 (2024) Abstr 11210 [www.page-meeting.org/?abstract=11210]
Poster: Drug/Disease Modelling - Other Topics