Roeland E. Wasmann1, Hylke Waalewijn2, David Burger2, Angela Colbers2, Diana Gibb3, Helen M. McIlleron1,4 ¶, Paolo Denti1¶
1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; 2 Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; 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
Objectives: T
Tenofovir alafenamide fumarate (TAF) is a prodrug of tenofovir (TFV). TAF is mainly metabolised intracellularly to TFV and subsequently to the active metabolite TFV diphosphate (TFV-DP). As a result of this intracellular conversion, lower systemic TFV concentrations are found compared to the widely used formulation tenofovir disoproxil fumarate (TDF), while the intracellular concentration of the active metabolite TFV-DP is higher. Therefore, TAF can be administered in a lower dose (300 mg of TDF versus 25 mg of TAF in adults). Lower TFV concentrations might be preferred since tenofovir plasma concentrations have been linked to renal and bone toxicity [1]. In the treatment of HIV, TAF is always combined with other drugs, therefore it is important to understand its pharmacokinetics (PK) to anticipate interactions. We aimed to build a semi-mechanistic model describing TAF and TFV plasma PK in children in the presence of ritonavir-boosted protease inhibitors (PIs) or dolutegravir.
Methods:
Data was available from a PK substudy nested within CHAPAS4, a randomised controlled trial (#ISRCTN22964075) evaluating practical TAF dosing in weight bands combined with 1 of 3 boosted PIs or dolutegravir. 919 children (3-15 years of age) failing on first-line treatment were randomised to TAF plus emtricitabine versus standard of care (abacavir or zidovudine plus lamivudine) and a third drug which was dolutegravir or a PI (atazanavir/r, darunavir/r or lopinavir/r). Children between 14 and 25 kg received 15 mg TAF, while children >25 kg received 25 mg TAF. PK sampling at 0, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after dose was performed at least 6 weeks after treatment initiation. TAF and TFV were quantified using a validated LC-MS/MS method with a lower limit of quantification of 0.5 mg/L for both. Data were analysed by non-linear mixed-effects modelling with NONMEM (v7.5.0). Samples below the limit of quantification (BLQ) were handled similar to the M6 method [2]. TAF and TFV were first modelled separately and joined either directly or with additional compartments representing the intracellular pathway of TAF. We assumed that TAF is ultimately completely transformed into TFV. Allometric scaling was applied to all clearance and volume parameters. The main covariates of interest were renal function on TFV clearance and the drug-drug interactions with dolutegravir or one of the boosted PIs on absorption and disposition parameters.
Results:
106 children (52.2% female) living with HIV with a median (range) age of 10.7 (3.83-15.7) and weight of 26.0 (14.2-53.0) kg were included in the analysis providing 957 TAF and 954 TFV concentrations. 484 TAF samples and 6 TFV samples had a concentration below the lower limit of quantification. TAF was best described using a one-compartment model with a volume of 19.6L, first-order absorption of 1.29 h-1 and 0.24 h lag time. TFV was best described with a two-compartment model with a central and peripheral volume of 149 L and 1100 L, respectively, and a 28.9 L/h clearance. The two models were connected via two routes, a fast and a slow route, both explaining disappearance of TAF and appearance of TFV in the respective central compartment. The fast route had a direct clearance of 20.4 L/h between the two central compartments, the slow route went via a “cellular” depot with a half-life of 6 h. The drug was then cleared into the central TFV compartment with a clearance of 129 L/h. All clearance and volume compartments were allometrically scaled with weight on 25 kg child. Renal clearance calculated using the Schwarz formula was added as a covariate on TFV clearance with a typical creatinine clearance of 121 ml/min (dOFV=-179, p<0.001) (3). Participants receiving PIs had a 50% lower TFV clearance compared to those in the dolutegravir arm (dOFV=-307, p<0.001). A visual predictive check indicated that the model described the data well.
Conclusions:
The semi-mechanistic model we developed was able to accurately describe TAF and TFV concentrations. This includes the peak concentration of TFV just after administration and the prolonged slow disappearance of TFV, which is mainly regulated by the slow release from the intracellular compartment. The model also allows for further investigations on drug-drug interactions that affect transporters and as a result, change the slow route either by changing the speed of removal of TAF or change the release of TFV into its central compartment.
References:
[1] Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic Review and Meta‐analysis: Renal Safety of Tenofovir Disoproxil Fumarate in HIV‐Infected Patients. Clin Infect Dis. 2010 Sep;51(5):496–505.
[2] Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28(5):481–504.
[3] Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976 Aug [cited 2022 Apr 8];58(2):259–63.
Reference: PAGE 30 (2022) Abstr 10153 [www.page-meeting.org/?abstract=10153]
Poster: Drug/Disease Modelling - Paediatrics