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1.
Clin Pharmacokinet ; 60(5): 569-583, 2021 05.
Article in English | MEDLINE | ID: mdl-33782830

ABSTRACT

Remdesivir (RDV, Veklury®) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug-drug interaction potential based on available in vitro and clinical data in healthy volunteers. Following single-dose intravenous administration over 2 h of an RDV solution formulation across the dose range of 3-225 mg in healthy participants, RDV and its metabolites (GS-704277and GS-441524) exhibit linear pharmacokinetics. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. Based on pharmacokinetic bridging from animal data and available human data in healthy volunteers, the RDV clinical dose regimen of a 200-mg loading dose on day 1 followed by 100-mg maintenance doses for 4 or 9 days was selected for further evaluation of pharmacokinetics and safety. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. Mathematical drug-drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug-drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , COVID-19 Drug Treatment , Adenosine/analogs & derivatives , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Adult , Alanine/pharmacokinetics , Alanine/pharmacology , Alanine/therapeutic use , Animals , Antiviral Agents/pharmacokinetics , Area Under Curve , Dose-Response Relationship, Drug , Drug Interactions , Furans/metabolism , Half-Life , Humans , Metabolic Clearance Rate , Pyrroles/metabolism , SARS-CoV-2 , Triazines/metabolism
2.
Antimicrob Agents Chemother ; 59(10): 6395-401, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26239974

ABSTRACT

The male genital tract is a potential site of viral persistence. Therefore, adequate concentrations of antiretrovirals are required to eliminate HIV replication in the genital tract. Despite higher zidovudine (ZDV) and lamivudine (3TC) concentrations in seminal plasma (SP) than in blood plasma (BP) (SP/BP drug concentration ratios of 2.3 and 6.7, respectively), we have previously reported lower relative intracellular concentrations of their active metabolites, zidovudine triphosphate (ZDV-TP) and lamivudine triphosphate (3TC-TP), in seminal mononuclear cells (SMCs) than in peripheral blood mononuclear cells (PBMCs) (SMC/PBMC drug concentration ratios of 0.36 and 1.0, respectively). Here, we use population pharmacokinetic (PK) modeling-based methods to simultaneously describe parent and intracellular metabolite PK in blood, semen, and PBMCs and SMCs. From this model, the time to steady state in each matrix was estimated, and the results indicate that the PK of 3TC-TP and ZDV-TP in PBMCs are different from the PK of the two in SMCs and different for the two triphosphates. We found that steady-state conditions in PBMCs were achieved within 2 days for ZDV-TP and 3 days for 3TC-TP. However, steady-state conditions in SMCs were achieved within 2 days for ZDV-TP and 2 weeks for 3TC-TP. Despite this, or perhaps because of it, ZDV-TP in SMCs does not achieve the surrogate 50% inhibitory concentration (IC50) (as established for PBMCs, assuming SMC IC50 = PBMC IC50) at the standard 300-mg twice-daily dosing. Mechanistic studies are needed to understand these differences and to explore intracellular metabolite behavior in SMCs for other nucleoside analogues used in HIV prevention, treatment, and cure.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Cytidine Triphosphate/analogs & derivatives , Dideoxynucleotides/pharmacokinetics , Lamivudine/analogs & derivatives , Leukocytes, Mononuclear/metabolism , Models, Statistical , Semen/metabolism , Thymine Nucleotides/pharmacokinetics , Zidovudine/analogs & derivatives , Adult , Anti-HIV Agents/pharmacology , Biological Availability , Biological Transport , Blood Cells/drug effects , Blood Cells/metabolism , Blood Cells/pathology , Blood Cells/virology , Computer Simulation , Cytidine Triphosphate/pharmacokinetics , Cytidine Triphosphate/pharmacology , Dideoxynucleotides/pharmacology , HIV Infections/drug therapy , HIV Infections/pathology , HIV Infections/virology , HIV-1/drug effects , HIV-1/physiology , Humans , Lamivudine/pharmacokinetics , Lamivudine/pharmacology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Male , Semen/cytology , Semen/drug effects , Semen/virology , Thymine Nucleotides/pharmacology , Time Factors , Zidovudine/pharmacokinetics , Zidovudine/pharmacology
3.
Antimicrob Agents Chemother ; 55(4): 1549-55, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21282432

ABSTRACT

Studies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2'-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/10(6) cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/10(6) cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Didanosine/pharmacokinetics , Didanosine/therapeutic use , HIV Infections/drug therapy , Nucleotides/blood , Organophosphonates/pharmacokinetics , Organophosphonates/therapeutic use , Adenine/pharmacokinetics , Adenine/therapeutic use , Adult , Aged , Chromatography, Liquid , Deoxyadenine Nucleotides/blood , Deoxyguanine Nucleotides/blood , Dideoxynucleotides/blood , Female , HIV Infections/blood , Humans , Male , Middle Aged , Tandem Mass Spectrometry , Tenofovir , Young Adult
4.
HIV Clin Trials ; 9(4): 213-24, 2008.
Article in English | MEDLINE | ID: mdl-18753116

ABSTRACT

OBJECTIVES: Evaluate efficacy, safety, tolerability, pharmacokinetics, adherence, and treatment satisfaction of atazanavir/ritonavir (ATV/r) 300 mg/100mg and tenofovir DF/emtricitabine (TDF/FTC) 300 mg/200mg once daily in antiretroviral-naïve HIV-infected patients. METHOD: Single-arm, open-label, multicenter 48-week study. RESULTS: 100 patients were evaluated; 17 patients discontinued early including 6 for adverse events. There were 2 deaths (multi-organ failure, lactic acidosis). At 48 weeks, 81% achieved HIV-1 RNA <50 copies/mL (ITT, M=F). No K65R or ATV/r associated mutations emerged; M184V developed in one patient. Median CD4 increase was 217 cells/mm3. The most common adverse events (> or = 10%) were diarrhea, nausea, scleral icterus, fatigue, upper respiratory tract infection, headache, and vomiting. Grade 4 hyperbilirubinemia occurred in 5%. Median increases at 48 weeks in total cholesterol, HDL, LDL, and triglycerides were 11, 3, 2, and 5 mg/dL, respectively. Two patients had confirmed graded increases in serum creatinine (one grade 1, one grade 2). Median (IQR) creatinine clearance change from baseline at 48 weeks was -7 (-19, 2) mL/min. Geometric mean (95% CI) ATV trough concentrations exceeded suggested therapeutic range. At 48 weeks, 92% of patients reported complete adherence by 1-week recall and 90% reported being "very satisfied" with the regimen. CONCLUSION: ATV/r+TDF/FTC was safe, well tolerated, and convenient for patients. Larger comparative trials are ongoing.


Subject(s)
Adenine/analogs & derivatives , Anti-HIV Agents , Deoxycytidine/analogs & derivatives , HIV Infections/drug therapy , HIV Infections/metabolism , HIV-1 , Oligopeptides , Organophosphonates , Pyridines , Ritonavir , Adenine/adverse effects , Adenine/pharmacokinetics , Adenine/therapeutic use , Adult , Aged , Anti-HIV Agents/adverse effects , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , Atazanavir Sulfate , Creatinine/blood , Deoxycytidine/adverse effects , Deoxycytidine/pharmacokinetics , Deoxycytidine/therapeutic use , Diarrhea/etiology , Drug Administration Schedule , Emtricitabine , Fatigue/etiology , Female , HIV Infections/blood , Humans , Hyperbilirubinemia , Jaundice/etiology , Male , Middle Aged , Nausea/etiology , Oligopeptides/adverse effects , Oligopeptides/pharmacokinetics , Oligopeptides/therapeutic use , Organophosphonates/adverse effects , Organophosphonates/pharmacokinetics , Organophosphonates/therapeutic use , Patient Compliance , Pyridines/adverse effects , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Respiratory Tract Infections/etiology , Ritonavir/pharmacokinetics , Ritonavir/therapeutic use , Tenofovir , Treatment Outcome , United States
5.
J Acquir Immune Defic Syndr ; 48(2): 156-62, 2008 Jun 01.
Article in English | MEDLINE | ID: mdl-18360288

ABSTRACT

OBJECTIVES: To quantitate extracellular and intracellular zidovudine (ZDV) and lamivudine (3TC) concentrations in blood and semen of HIV-1-infected men. DESIGN: : Nonblind, single-center, open-label pharmacokinetic (PK) study in 14 subjects receiving ZDV plus 3TC. METHODS: Paired blood and semen samples were obtained during 1 intensive visit and 3 single time point visits over 2 weeks. Extracellular ZDV and 3TC concentrations were measured in blood plasma (BP) and seminal plasma (SP), and intracellular ZDV and 3TC triphosphate (TP) concentrations were measured in isolated mononuclear cells using validated methods. HIV-1 RNA was measured in blood and semen. PK parameters were estimated using noncompartmental analysis. RESULTS: Median (interquartile range [IQR]) SP/BP area under the time-concentration curve over the 12-hour dosing interval (AUC0-12h) ratios for ZDV and 3TC were 2.28 (1.48 to 2.97) and 6.67 (4.10 to 9.14), respectively, whereas individual SP/BP concentration ratios ranged from 1.9 to 91.4. Intracellular median (IQR) SP/BP AUC0-12h ratios for ZDV-TP and 3TC-TP were 0.36 (0.30 to 0.37) and 1.0 (0.62 to 1.30), respectively, whereas individual SP/BP concentration ratios ranged from 0.11 to 2.9. HIV-1 RNA was undetectable in both compartments. CONCLUSIONS: ZDV and 3TC SP exposures are 2- to 6-fold greater than BP exposures. Seminal ZDV-TP exposures are approximately 40% of those found in peripheral blood mononuclear cells (PBMCs), whereas 3TC-TP exposures are similar to PBMC exposures. PK variability makes individual SP/BP ratios a suboptimal surrogate for genital tract exposure.


Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/pharmacokinetics , Extracellular Fluid/metabolism , HIV-1 , Intracellular Fluid/metabolism , Lamivudine/pharmacokinetics , Semen/metabolism , Zidovudine/pharmacokinetics , Acquired Immunodeficiency Syndrome/metabolism , Adult , Area Under Curve , CD4 Lymphocyte Count , Humans , Male , RNA, Viral/analysis
6.
Antimicrob Agents Chemother ; 51(12): 4284-9, 2007 Dec.
Article in English | MEDLINE | ID: mdl-17923489

ABSTRACT

GSK364735 is a human immunodeficiency virus (HIV) integrase strand transfer inhibitor with potent in vitro antiviral activity. This study was a double-blind, randomized, placebo-controlled, dose escalation, phase I study to assess single- and repeated-dose safety, tolerability, pharmacokinetics (PK), and food effect of GSK364735 in healthy subjects. In part A, three alternating cohorts of 10 subjects (8 receiving the active drug and 2 receiving a placebo) received single doses of 50 to 400 mg while fasting or 200 mg and 400 mg coadministered with food. In part B, five cohorts received repeated doses of 100 to 600 mg daily coadministered with food for 8 days. Safety was assessed throughout the study. Serial blood samples were analyzed for GSK364735 plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. PK parameters were estimated using noncompartmental methods. Seventy-nine (30 in part A and 49 in part B) subjects were enrolled and received GSK364735 or placebo. GSK364735 was readily absorbed following oral dose administration, with the maximum concentration achieved between 0.75 to 5.0 h postdose. GSK364735 exposure increased less than dose proportionally, demonstrated wide variability, and appeared to reach a plateau at 100- to 200-mg doses. Food increased GSK364735 exposure by 28 to 91%. GSK364735 was safe and well tolerated after single- and repeated-dose administration. No serious or severe adverse events (AEs) or AEs leading to withdrawal and few drug-related AEs were reported. Despite solubility-limited absorption, GSK364735 exceeded therapeutic trough concentrations for the majority of doses studied. The PK and safety profile supported the continued investigation of GSK364735 in HIV-infected subjects.


Subject(s)
HIV Integrase Inhibitors/pharmacokinetics , HIV-1/drug effects , Adolescent , Adult , Area Under Curve , Cohort Studies , Dizziness/chemically induced , Dose-Response Relationship, Drug , Double-Blind Method , Female , Food , HIV Integrase Inhibitors/administration & dosage , HIV Integrase Inhibitors/adverse effects , Headache/chemically induced , Humans , Male , Middle Aged
7.
Antimicrob Agents Chemother ; 51(4): 1202-8, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17261626

ABSTRACT

Brecanavir (BCV) is a novel, potent protease inhibitor in development for the treatment of human immunodeficiency virus (HIV-1) infection with low nM in vitro 50% inhibitory concentrations (IC50s) against many multiprotease inhibitor resistant viruses. This study was a double-blind, randomized, placebo-controlled repeat-dose escalation to evaluate the safety, tolerability, and pharmacokinetics of BCV, with or without ritonavir (RTV), in 68 healthy subjects. Seven sequential cohorts (n=10) received BCV (50 to 600 mg) in combination with 100 mg RTV (every 12 h [q12h] or q24h) or alone at 800 mg q12h for 15 days. BCV alone or in combination with RTV was well tolerated, with no serious adverse events reported. The most common drug-related adverse event was headache. BCV was readily absorbed with median time to maximum concentration of drug in serum values ranging from 2.5 to 5.0 h postdose following single- and repeat-dose administration of BCV alone and BCV with RTV 100 mg. Geometric mean BCV accumulation ratios ranged from 1.4 to 1.56 following BCV-RTV q24h regimens and from 1.84 to 4.93 following BCV q12h regimens. BCV steady state was generally achieved by day 13 in all groups. All day 15 BCV-RTV trough concentration values in q12h regimens reached or surpassed the estimated protein-binding corrected in vitro IC50 target BCV concentration of 28 ng/ml for highly resistant isolates. The pharmacokinetic and safety profile of BCV-RTV supports continued investigation in HIV-1-infected subjects.


Subject(s)
Benzodioxoles/adverse effects , Benzodioxoles/pharmacokinetics , Carbamates/adverse effects , Carbamates/pharmacokinetics , HIV Infections/drug therapy , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/therapeutic use , Adult , Area Under Curve , Benzodioxoles/blood , Carbamates/blood , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Combinations , Female , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/pharmacokinetics , HIV-1/drug effects , Humans , Male , Middle Aged , Ritonavir/administration & dosage , Ritonavir/blood , Safety
8.
Antimicrob Agents Chemother ; 50(6): 2201-6, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16723584

ABSTRACT

Brecanavir (BCV, 640385) is a novel, potent protease inhibitor (PI) with low nanomolar 50% inhibitory concentrations against PI-resistant human immunodeficiency virus (HIV) in vitro. This phase I, double-blind, randomized, placebo-controlled, two-part single-dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of BCV administered at 10 mg/ml in a tocopherol-polyethylene glycol succinate-polyethylene glycol 400-ethanol 50:40:10 solution. In part 1 of the study, single oral doses of BCV ranged from 25 mg to 800 mg. In part 2, single oral doses of BCV ranged from 10 mg to 300 mg and were coadministered with 100-mg oral ritonavir (RTV) soft gel capsules. Single doses of BCV and BCV/RTV were generally well tolerated. There were no severe adverse events (SAEs), and no subject was withdrawn due to BCV. The most commonly reported drug-related AEs during both parts of the study combined were gastrointestinal disturbances (similar to placebo) and headache. BCV was readily absorbed following oral administration with mean times to maximum concentration from >1 h to 2.5 h in part 1 and from 1.5 h to 3 h in part 2. Administration of BCV without RTV resulted in BCV exposures predicted to be insufficient to inhibit PI-resistant virus based on in vitro data. Coadministration of 300 mg BCV with 100 mg RTV, however, significantly increased the plasma BCV area under the concentration-time curve and maximum concentration 26-fold and 11-fold, respectively, achieving BCV concentrations predicted to inhibit PI-resistant HIV.


Subject(s)
Benzodioxoles/administration & dosage , Benzodioxoles/pharmacokinetics , Carbamates/administration & dosage , Carbamates/pharmacokinetics , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Benzodioxoles/adverse effects , Benzodioxoles/blood , Capsules , Carbamates/adverse effects , Carbamates/blood , Diarrhea/chemically induced , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Drug Combinations , Flatulence/chemically induced , Gels , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/blood , Half-Life , Headache/chemically induced , Humans , Male , Middle Aged , Nausea/chemically induced , Ritonavir/administration & dosage , Ritonavir/blood
10.
J Infect Dis ; 186(9): 1339-43, 2002 Nov 01.
Article in English | MEDLINE | ID: mdl-12402205

ABSTRACT

Therapeutic concentrations of antiretroviral agents in seminal plasma (SP) may reduce virus burden and influence sexual transmission of human immunodeficiency virus (HIV) type 1. This study compared the pharmacokinetic, pharmacodynamic, and dose responses of efavirenz (EFV) in SP versus those in blood plasma (BP). A total of 431 BP samples and 157 SP samples were obtained over a period of 40 days, from 9 EFV-naive men (i.e., men about to receive EFV for the first time) and from 12 EFV-experienced men (i.e., men already receiving EFV as part of an antiretroviral regimen). Overall, median EFV exposure in SP was 3.4% (range, 2.0%-5.0%) of that in BP. However, all EFV concentrations in SP were >/=40-fold higher than the wild-type IC(90) (IC(90)(WT)) for HIV-1. During the dosing interval, no single SPrcolon;BP EFV-concentration ratio was significantly predictive of the absolute measure of exposure in SP. By day 40, HIV-1 RNA in SP was undetectable in 8 (89%) of 9 EFV-naive men and remained undetectable in 10 (83%) of 12 EFV-experienced men. In SP, EFV reaches concentrations above the HIV-1 IC(90)(WT) throughout the dosing interval. EFV-containing regimens effectively suppress HIV-1 RNA in SP.


Subject(s)
Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/pharmacokinetics , HIV Infections/drug therapy , Oxazines/pharmacokinetics , Semen/metabolism , Acquired Immunodeficiency Syndrome/blood , Adult , Alkynes , Anti-HIV Agents/blood , Anti-HIV Agents/therapeutic use , Benzoxazines , Cyclopropanes , HIV Infections/blood , HIV-1 , Humans , Male , Metabolic Clearance Rate , Oxazines/blood , Oxazines/therapeutic use
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