Aida N Kawuma (1), Roeland E Wasmann (1), Phumla Sinxadi (1), Simiso M Sokhela (2), Nomathemba Chandiwana (2), Willem DF Venter (2), Lubbe Wiesner (1), Gary Maartens (1,3), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. (2) Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. (3) Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
Objectives:
Tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are prodrugs of tenofovir, a nucleoside analogue that inhibits human immunodeficiency virus (HIV) replication. Tenofovir is activated intracellularly to tenofovir-diphosphate (TFV-DP). TDF-based antiretroviral regimens remain among the most widely prescribed because of TDF‘s effective antiviral activity, favourable safety profile, low potential for resistance and availability within several fixed-dose co-formulated tablets.1 However, while TDF is generally well tolerated, it leads to higher plasma tenofovir concentrations than TAF, resulting in the potential for kidney injury.2–5 Conversely, TAF more efficiently delivers tenofovir to HIV-target cells leading to higher intracellular TFV-DP and lower plasma tenofovir concentrations. The World Health Organization HIV treatment guidelines recommend TAF (instead of TDF) for adults with established osteoporosis and/or impaired kidney function. We aimed to use a single model to jointly describe the population pharmacokinetics of tenofovir, given as TAF or TDF, in Africans living with HIV.
Methods:
Tenofovir concentration-time data were available from a pharmacokinetic sub-study nested within the ADVANCE study (NCT03122262), an open-label, phase 3, randomized non-inferiority trial in Southern African adults. Full study procedures have been reported previously.6 Rich sampling at steady state was performed at 0, 1, 2, 4, 6, 8, and 24-hours post-dose. Tenofovir was quantified using a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification of 0.0005 mg/L.7
Data were analyzed by non-linear mixed-effects modelling with NONMEM (v7.5.0) using the first-order conditional estimation with interaction method. First, the model was developed with data from the TDF arm alone and subsequently, we added data from the TAF arm. We explored one- and two-compartment disposition models with first-order elimination and absorption, with or without absorption lag time and transit compartments.8 We also explored different semi-mechanistic models to describe the absorption of tenofovir administered as TAF. The release of tenofovir after TAF was described with a bi-phasic absorption pathway with an estimated fast fraction (FFast) available for immediate absorption into systemic circulation while a slow fraction (FSlow) was modelled as if it was first absorbed intracellularly and then slowly transitioned to the systemic circulation, mimicking the intracellular decay of TFV-DP back to tenofovir. We aimed to estimate the half-life of this transition (T1/2(transition)). Allometric scaling with weight was added to all clearance and volume parameters. 9
Results: Forty-one individuals provided 279 tenofovir concentrations. Median (interquartile range) weight and age were 73.1 (67.2–85.2) kg and 31 (29–36) years, respectively. A two-compartment disposition model (ΔOFV=-47, p<0.001 compared to one-compartment) best described the pharmacokinetics of tenofovir. We estimated (95%CI) clearance of 44.7 (40.2–49.5) L/h, central volume of 378 (318–459) L, peripheral volume of 356 (298–438) L, and FFast of 32.4 (27.0–37.7)% for a typical individual of 70 kg. While we aimed to estimate T1/2(transition), the value fluctuated widely, and after a likelihood profiling exercise, it was clear that given the available data, the model couldn’t estimate it with sufficient certainty. Therefore, we fixed it to 6.8 days; the half-life previously reported for intracellular decay of TFV-DP.10 A visual predictive check shows that the final model described the observed data adequately, with the median, 5th, and 95th percentiles of the observed data falling within the 95% confidence interval of the respective prediction.
Conclusions:
We developed a semi-mechanistic model that describes the population pharmacokinetics of tenofovir. We jointly described tenofovir disposition when dosed as either TDF or TAF unlike previous reports in which two separate models have been reported for tenofovir; based on the prodrug administered.11 Our model, developed in an African population, can be used as a tool for exposure prediction in patients, for simulation of alternative regimens and for sample size calculations for further clinical trials that may increasingly involve the use of TAF as it replaces TDF.
References:
[1] Estrella, M. M., Moosa, M. R. & Nachega, J. B. Editorial Commentary: Risks and Benefits of Tenofovir in the Context of Kidney Dysfunction in Sub-Saharan Africa. Clin. Infect. Dis. 58, 1481–1483 (2014).
[2] Tourret, J., Deray, G. & Isnard-Bagnis, C. Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? J. Am. Soc. Nephrol. 24, 1519–1527 (2013).
[3]Scherzer, R. et al. Association of Tenofovir Exposure with Kidney Disease Risk in HIV Infection. AIDS 26, 867 (2012).
[4]Cooper, R. D. et al. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin. Infect. Dis. 51, 496–505 (2010).
[5]Agbaji, O. O. et al. Long Term Exposure to Tenofovir Disoproxil Fumarate-Containing Antiretroviral Therapy Is Associated with Renal Impairment in an African Cohort of HIV-Infected Adults. J. Int. Assoc. Provid. AIDS Care 18, 1–9 (2019).
[6]Venter, W. D. F. et al. Dolutegravir plus Two Different Prodrugs of Tenofovir to Treat HIV. N. Engl. J. Med. 381, 803–815 (2019).
[7]Phillips, T. K. et al. A comparison of plasma efavirenz and tenofovir, dried blood spot tenofovir-diphosphate, and self-reported adherence to predict virologic suppression among South African women. J. Acquir. Immune Defic. Syndr. 81, 311 (2019).
[8]Savic, R. M., Jonker, D. M., Kerbusch, T. & Karlsson, M. O. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J.
[9]Janmahasatian, S. et al. Quantification of lean bodyweight. Clin. Pharmacokinet. 44, 1051–1065 (2005).
[10]Jackson, A. et al. Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: Implications for HIV treatment and prevention. J. Acquir. Immune Defic. Syndr. 62, 275–281 (2013).
[11]Greene, S. A. et al. Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen. Clin. Pharmacol. Ther. 106, 821–830 (2019).
Reference: PAGE 30 (2022) Abstr 10031 [www.page-meeting.org/?abstract=10031]
Poster: Drug/Disease Modelling - Infection