Pharmacokinetics and renal safety of tenofovir alafenamide with boosted protease inhibitors and ledipasvir/sofosbuvir

Abstract

Background Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir. Objectives To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs. Methods Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and β2 microglobulin (β2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit. Results Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and β2M:creatinine improved following the switch to TAF. Conclusions Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations.

Pharmacokinetics of Tenofovir Alafenamide With Boosted Protease Inhibitors in Pregnant and Postpartum Women Living With HIV: Results From IMPAACT P1026s

“…However, TAF is the predominant moiety that loads target cells, 40 not tenofovir [40][41][42] ; thus, our findings are still important for better understanding TAF PK and efficacy in pregnancy. From a safety perspective, plasma tenofovir AUC tau is ;75%-90% lower with TAF vs. TDF in nonpregnant adults, 7,8,10 and a similar magnitude of difference was separately observed in pregnant and postpartum women with HIV. 19 Further assessments of the parent tenofovir form in plasma and intracellular tenofovir diphosphate in peripheral blood mononuclear cells and dried blood spots will be critical to informing TAF use during pregnancy, 43 and these will be examined in the next iteration of this study.…”

“…Both prodrugs yield the same active moiety, tenofovir diphosphate, within cells, but the pharmacology and safety profiles of the 2 drugs differ markedly. [6][7][8][9][10] TDF is administered at a 300-mg dose in adults and adolescents with HIV. 11 TAF dosing varies depending on the concomitant antiretroviral medications and region of use: In the United States, it is administered as either a 10-mg dose in cobicistat-containing fixed-dose combinations 12,13 or a 25mg dose with all other antiretroviral combinations in adults, 14 and in Europe, TAF is administered as a 10-mg dose with all cobicistat-containing or ritonavir-containing regimens and 25 mg without a pharmacoenhancer.…”

“…15 TAF yields ;75%-90% lower plasma tenofovir area under the concentration-time curve over the dosing interval (AUC tau ) and ;2-fold-10-fold higher tenofovir-diphosphate concentrations in peripheral blood mononuclear cells. 7,8,10 In recent years, patterns of clinical use have shifted toward TAFcontaining regimens in the United States, 16 and this will likely increase globally as access expands. 3,17 However, data supporting TAF use during pregnancy have lagged behind nonpregnant adults, with guidelines only recently conditionally recommending its use.…”

A Systematic Literature Review on the Use of Dried Biofluid Microsampling in Patients With Kidney Disease

“…Only pazopanib showed significant differences between collection methods with a 48% lower concentration reported with matched DBS [ 50 ]. Furthermore, to ensure drug adherence and/or safety, three studies quantified tenofovir (a nucleotide reverse transcriptase inhibitor) in DBS [ 25 , 52 , 53 ]. A further study measured both tenofovir and emtricitabine concentrations using a single DBS [ 53 ].…”

Evidence for Implementation: HIV/HCV Coinfection and Pregnancy

“…The first HCV DAAs were FDA-approved in 2015; however, the first pharmacokinetic study of these antivirals in pregnancy was published in 2020. Despite ample data regarding the pharmacokinetic interactions between DAAs and ART in the general population with HIV/HCV coinfection, there have been no studies evaluating important drug interactions during pregnancy when pharmacokinetics are impacted by physiologic changes [ 69 – 71 ]. We must chart a path forward that includes rigorous evaluation of the safety and efficacy of interventions important to pregnancy.…”