Paolo Denti (1), Charles Flexner (2), Paul Pham (2), Lawrence Lee (3)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, (2) Department of Medicine, Johns Hopkins University, Baltimore, MD, USA, (3) Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Objectives: Ritonavir-boosted darunavir (DRV/r) with efavirenz (EFV) is an alternative nucleoside-sparing regimen for HIV treatment. The metabolic pathways involved in the pharmacokinetics of these drugs are intertwined and complex drug-drug interactions are expected. We have previously shown that efavirenz induces the metabolism of darunavir but the inhibitory effects of ritonavir ensure that the drug concentrations are still adequate to treat patients without darunavir drug resistance mutations, at a once daily dose [1]. We aim to develop a population model to characterize these interactions and help make predictions about possible dosing regimens.
Methods: Twelve healthy volunteers were included in the study and blood samples were collected across 38 days. DRV/r (900/100 mg once daily) was administered alone for 10 days, on day 11 EFV (600 mg once daily) was started, and on day 24 DRV/r was stopped and EFV continued for another 14 days. Intensive blood sampling was performed on day 10, 11, 24, and 38, and additional trough samples were collected every 4-5 days in between [1]. An integrated population pharmacokinetic model describing the interaction of darunavir (DRV) and ritonavir (RTV) was created in NONMEM 7, characterising between-subject (BSV) and -occasion variability (BOV) in the PK parameters. An independent model was also designed for EFV, whose effect on DRV and RTV was modelled as dichotomous. Allometric scaling was applied to adjust for body size [2]. Visual predictive checks and the objective function value were used during model development.
Results: For all three drugs the structural model was a 2-compartment disposition with transit compartment absorption [3]. There was a strong correlation between the variability for absorption and elimination parameters at BOV level for DRV and RTV. The dynamic effect of RTV concentration on DRV CL was modelled with a sigmoidal function, which improved the model fit and provided DRV CL values of ~6L/h for the range of observed RTV concentrations. The typical value of DRV CL in absence of RTV (a scenario not observed in this dataset) was fixed to the value of ~33 L/h, reported by Sekar et al. [4], and the model estimated a low value of RTV EC50 (<70 ng/mL, the assay limit of quantification). EFV co-administration was found to increase the CL of DRV and RTV by more than 15%. CL of EFV decreased by about 30% for each CYP2B6 *6 allele, with respect to homozygous wild type.
Conclusions: The low value of RTV EC50 indicates the potency of RTV as an inhibitor, which was already highly active at low concentrations. This suggests that a reduction in RTV dose could preserve its inhibitory effect on DRV CL, as long as the concentration is kept above the (low) active concentration. A RTV dose reduction in DRV/r has been previously advocated by Hill et al. [5]. This strategy could be possible as RTV is now a generic drug and future RTV formulations may include lower doses like 50 mg. The further integration of EFV in the combined model could help separate the expected RTV inhibition effect on EFV CL and the EFV auto-induction effect.
References:
[1] G. H. Soon, P. Shen, E.-L. Yong, P. Pham, C. Flexner, and L. Lee, “Pharmacokinetics of darunavir at 900 milligrams and ritonavir at 100 milligrams once daily when coadministered with efavirenz at 600 milligrams once daily in healthy volunteers.,” Antimicrobial agents and chemotherapy, vol. 54, no. 7, pp. 2775-80, Jul. 2010.
[2] B. J. Anderson and N. H. G. Holford, “Mechanism-based concepts of size and maturity in pharmacokinetics.,” Annual review of pharmacology and toxicology, vol. 48, pp. 303-32, Jan. 2008.
[3] R. M. Savic, D. M. Jonker, T. Kerbusch, and M. O. Karlsson, “Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies.,” Journal of pharmacokinetics and pharmacodynamics, vol. 34, no. 5, pp. 711-26, Oct. 2007.
[4] V. Sekar, S. Guzman, T. Stevens, E. De Paepe, L. E, and R. Hoetelmans, “Absolute bioavailability of TMC114, administered in the absence and presence of low-dose ritonavir,” in Program and abstracts of 7th International Workshop on Pharamacology of HIV Therapy, 2006, Abstract 86.
[5] A. Hill, J. van der Lugt, W. Sawyer, and M. Boffito, “How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials.,” AIDS (London, England), vol. 23, no. 17, pp. 2237-45, Nov. 2009.
Reference: PAGE 21 () Abstr 2497 [www.page-meeting.org/?abstract=2497]
Poster: Infection