Pilot Pharmacokinetic Study of Human Immunodeficiency Virus-Infected Patients Receiving Tenofovir Disoproxil Fumarate (TDF): Investigation of Systemic and Intracellular Interactions between TDF and Abacavir, Lamivudine, or Lopinavir-Ritonavir

Abstract

Previous work has demonstrated the existence of systemic interaction between tenofovir (TFV) disoproxil fumarate (TDF) and didanosine as well as between TDF and lopinavir-ritonavir (LPV/r). Here we investigated TDF interactions with the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and abacavir (ABC), comparing both the concentrations of nucleoside/nucleotide reverse transcriptase inhibitors in plasma and the intracellular concentrations of their triphosphate metabolites (NRTI-TP) for human immunodeficiency virus-infected patients receiving these NRTIs with TDF and after 4 weeks of TDF interruption. We also looked at interactions between TDF-ABC and LPV/r, comparing patients receiving or not receiving LPV/r. Blood samples were taken at baseline and at 1, 2, and 4 h after dosing. Liquid chromatography-tandem mass spectrometry was used to measure NRTIs and NRTI-TPs. Statistical analyses were performed on pharmacokinetic parameters: the area under the concentration-time curve from 0 to 4 h (AUC 0-4 ), the maximum concentration of the drug (C max ), and the residual concentration of the drug at the end of the dosing interval (C trough ) for plasma and the AUC 0-4 and C trough for intracellular data. Among the groups of patient discontinuing TDF, the very long intracellular half-life of elimination (150 h) of TFV-DP (the diphosphorylated metabolite of TFV, corresponding to a triphosphorylated species) was confirmed. Comparison between groups as well as the longitudinal study showed no significant systemic or intracellular interaction between TDF and ABC or 3TC. Significant differences were observed between patients receiving LVP/r and those receiving nevirapine. For ABC, plasma exposure was decreased (40%) under LVP/r, while, in contrast, plasma exposure to TFV was increased by 50% and the intracellular TFV-DP AUC 0-4 was increased by 59%. A trend for a gender effect was observed for TFV-DP at the intracellular level, with higher and C trough values for women.Highly active antiretroviral therapy regimens include at least three antiretroviral agents combining a nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI] backbone with a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) (51). The issue of drug-drug interaction between NRTIs, including N(t)RTIs, and also between N(t)RTIs and PIs or NNRTIs needs to be addressed (37).All these drugs or prodrugs could interact at the systemic level (absorption, metabolism, distribution, or elimination) or at the cellular level through membrane transport, or through intracellular metabolism for the N(t)RTIs.Several in vitro and in vivo intracellular interactions have been reported between NRTIs sharing the same metabolic pathways for thymidine analogues (14, 17) and for cytidine analogues (24).More recently, a significant interaction between didanosine (ddI) and tenofovir (TFV) disoproxil fumarate (TDF) has been clinically demonstrated (6,23,29,32), showing a higher plasma exposure to ddI when it is combined with TD...

Pharmacokinetics of Lamivudine and Lamivudine-Triphosphate after Administration of 300 Milligrams and 150 Milligrams Once Daily to Healthy Volunteers: Results of the ENCORE 2 Study

“…Both doses were well tolerated, and no unexpected or serious adverse events related to the study medication were reported. The steady-state plasma 3TC and intracellular 3TC-TP pharmacokinetic parameters observed in the present study with 300 mg QD were comparable to that previously reported in healthy volunteers (2,3,28) and HIV-infected patients (2,9,14,17,18,21) receiving 3TC doses at 300 mg QD or 150 mg BID. However, there was marked intersubject variation in 3TC-TP concentrations, both here and in previous studies (the CV% invariably exceeded 50%), and differences between study centers, with some reporting slightly higher 3TC-TP concentrations (6 to 11 pmol/10 6 cells) in HIV-infected patients (13,21).…”

“…The steady-state plasma 3TC and intracellular 3TC-TP pharmacokinetic parameters observed in the present study with 300 mg QD were comparable to that previously reported in healthy volunteers (2,3,28) and HIV-infected patients (2,9,14,17,18,21) receiving 3TC doses at 300 mg QD or 150 mg BID. However, there was marked intersubject variation in 3TC-TP concentrations, both here and in previous studies (the CV% invariably exceeded 50%), and differences between study centers, with some reporting slightly higher 3TC-TP concentrations (6 to 11 pmol/10 6 cells) in HIV-infected patients (13,21). Such variability in nucleoside triphosphate concentrations may be attributed to a number of interrelated factors that relate to the patient/host (immune status, cellular function, and genetic variation) intracellular pharmacokinetics (endogenous enzyme activity, competition with endogenous deoxynucleoside triphosphates, and concomitantly administered drugs) and differences in bioanalytical methods.…”

Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention

“…12 A potential biologic cause may be a pharmacokinetic interaction between lopinavir-ritonavir and tenofovir; decreased renal clearance of tenofovir and increased plasma and intracellular levels, particularly in women, have been reported with concomitant administration. [13][14][15] In the PROMISE trial, the lopinavir-ritonavir dose was increased during the third trimester because pharmacokinetic studies showed decreased lopinavir-ritonavir levels with standard doses in late pregnancy. 16,17 The ART regimens in the PROMISE trial were protease inhibitor-based because nevirapinebased ART was contraindicated in women with a CD4 count of more than 250 cells per cubic millimeter, and efavirenz, the other available nonnucleoside reverse-transcriptase inhibitor (NNRTI), was contraindicated in pregnancy at that time.…”

Detection of Simian Immunodeficiency Virus in Semen, Urethra, and Male Reproductive Organs during Efficient Highly Active Antiretroviral Therapy

“…TFV, FTC, TFV-DP, FTC-TP, LPV, RTV, and RAL from extract samples were quantified using a Waters Acquity ultraperformance liquid chromatography (UPLC) system with a 2.1-by 100-mm, 1.7-m Acquity UPLC BEH RP18 shield column coupled to a Waters Xevo TQ-MS mass spectrometer operated in positive ion electrospray multiple-reaction-monitoring (MRM) mode. Two chromatographic conditions were used, one for FTC and TFV and another one for RTV, LPV, RAL, TFV-DP, and FTC-TP, both adapted from previously published methods (105,106).…”