Lufina Tsirizani (1,2), Roeland E. Wasmann (1), Hylke Waalewijn (1), Alexander Szubert (3), Helen M. McIlleron (1,4), David M. Burger (5), Diana M. Gibb (3), Angela Colbers (5), Paolo Denti (1), the CHAPAS-4 trial team.
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. (2) Training and Research Unit of Excellence, Kamuzu University of Health Sciences, Malawi. (3) Medical Research Council Clinical Trials Unit at University College London, London, United Kingdom. (4) Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. (5) Department of Pharmacy, Radboudumc Research Institute for Medical Innovation (RIMI), Radboud University Medical Center, Nijmegen, the Netherlands
Introduction: Ritonavir is a protease inhibitor (PI) with activity against HIV [1]. Due to its neurological and gastrointestinal side effects, its use has been limited to boost the exposures of other PIs [2], so that they can be administered at lower doses and less frequently [1]. Ritonavir strongly inhibits gut and liver CYP3A4 as well as the activity of P-glycoprotein efflux transporter [3]. It is highly protein bound and is also cleared by CYP3A4. Ritonavir-boosted PIs are pivotal in pediatric antiretroviral therapy (ART) [4]. However, despite their widespread use and significance in pediatric ART, data on ritonavir pharmacokinetics in children are notably scarce.
Methods: We investigated the population pharmacokinetics of ritonavir dosed according to weight and given to boost exposures of either twice-daily lopinavir, once-daily atazanavir, or once-daily darunavir. We used data from CHAPAS-4, a 2×4 factorial randomized study investigating the safety and acceptability of simple novel second-line antiretroviral regimens (ISRCTN22964075), in which the PIs were co-administered with nucleoside reverse transcriptase inhibitors (NRTIs) either tenofovir alafenamide/emtricitabine (TAF/FTC), abacavir/lamivudine (ABC/3TC), or zidovudine/lamivudine (AZT/3TC) in African children. Blood samples were collected pre-dose, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after morning dose, six weeks after randomization. Ritonavir was quantified using LC-MS/MS with a lower limit of quantification (LLOQ) of 0.0450 mg/L.
We investigated one- and two- compartment disposition models with zero- or first-order absorption (with and without lag time or transit compartments), first-order elimination with or without first-pass metabolism. Between-subject variability (BSV) was included on disposition parameters and between-occasion variability (BOV) on absorption parameters. Allometric scaling of clearance (with a fixed exponent of 0.75) and volume (with a fixed exponent of 1) parameters was tested with either total body weight or fat-free mass [5].
The effect of age on clearance and bioavailability of ritonavir was tested as a linear, power or exponential function. We examined the effect boosted PIs and NRTI backbone as categorical covariates on either absorption and/or disposition parameters, and we evaluated the diurnal variation in ritonavir pharmacokinetics after drug administration by comparing the differences in drug exposure after morning vs. evening ritonavir doses.
Results: 170 children (59 darunavir/ritonavir, 60 atazanavir/ritonavir, and 51 lopinavir/ritonavir) were enrolled in ritonavir-boosted PI arms of the CHAPAS-4 pharmacokinetic sub-study. Of 1254 ritonavir concentrations, 6.9% were below the LLOQ, and were mostly pre-dose. Median age and weight were 10.6 (range 3.2-15.6) years and 26.0 (14.2-64.2) kg respectively, 56% were female. A two-compartment disposition model with lag time in absorption followed by sequential zero- and first-order absorption best described ritonavir concentration-time data. The typical values of clearance and central volume of distribution in a 26 kg child were 10.5 Liters/hour and 54.5 Liters respectively. The average lag time in absorption was 0.98 hours. Fat-free mass based allometric scaling of clearance and volume parameters was preferred over weight-based scaling.
Compared to children on darunavir/ritonavir, those on atazanavir/ritonavir had 137% higher bioavailability and those on lopinavir/ritonavir had 23% less bioavailability. We observed 20.7% higher ritonavir clearance in those on atazanavir/ritonavir compared to the rest of the children in the analysis. Taking ritonavir at night led to a 3.6-fold slower absorption than during the day. After accounting for these effects, we found no significant effect of NRTI backbone or age.
Conclusions: Exposure to ritonavir displays variability among boosted PIs. While the precise etiology of these phenomenon may need further investigation, it is anticipated that atazanavir will increase the exposure of other PIs including ritonavir. We also hypothesize that there might be differences in affinity to CYP3A4 and P-glycoprotein transporters between the boosted PIs that may lead to differences in ritonavir exposure. NRTI backbones had no significant effect on ritonavir exposure. Our model can be used to predict ritonavir exposures when given with other ARTs, thereby reinforcing the evidence base for its use in pediatric populations.
References:
[1] Kappelhoff BS, Huitema ADR, Crommentuyn KML, Mulder JW, Meenhorst PL, Van Gorp ECM, et al. Development and validation of a population pharmacokinetic model for ritonavir used as a booster or as an antiviral agent in HIV-1-infected patients. Br J Clin Pharmacol. 2005;59(2):174–82.
[2] Gatti G, Di Biagio A, Casazza R, De Pascalis C, Bassetti M, Cruciani M, et al. The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS. 1999 Oct;13(15):2083–9.
[3] van Heeswijk RP, Veldkamp A, Mulder JW, Meenhorst PL, Lange JM, Beijnen JH, et al. Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. Antivir Ther. 2001 Dec;6(4):201–29.
[4] World Health Organization. Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring : recommendations for a public health approach. 2021. 548 p.
[5] Anderson BJ, Holford NHG. Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48(1):303–32.
Reference: PAGE 32 (2024) Abstr 11169 [www.page-meeting.org/?abstract=11169]
Poster: Drug/Disease Modelling - Paediatrics