ABSTRACT
To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.
Subject(s)
Alkynes/blood , Alkynes/therapeutic use , Benzoxazines/blood , Benzoxazines/therapeutic use , Cyclopropanes/blood , Cyclopropanes/therapeutic use , HIV Infections/blood , HIV Infections/drug therapy , Vitamin D/pharmacology , Vitamins/pharmacology , Adult , Cohort Studies , Female , Humans , Italy , Male , Middle Aged , Retrospective Studies , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/therapeutic use , Seasons , Treatment Outcome , Vitamin D/blood , Vitamins/bloodABSTRACT
We demonstrate the suitability of a fast, green, easy-to-perform, and modified sample extraction procedure, i.e., dispersive liquid-liquid microextraction (DLLME) for the determination of efavirenz (EFV) in human plasma. Data acquisition was done by gas chromatography-mass spectrometry (GC-MS) in the selected ion monitoring (SIM) mode. The simplicity of the method lies in, among others, the avoidance of the use of large organic solvent volumes as mobile phases and non-volatile buffers that tend to block the plumbing in high-performance liquid chromatography (HPLC). Chromatographic and mass spectral parameters were optimized using bovine whole blood for matrix matching due to insufficient human plasma. Method validation was accomplished using the United States Food and Drug Administration (USFDA) 2018 guidelines. The calibration curve was linear with a dynamic range of 0.10-2.0 µg/mL and an R2 value of 0.9998. The within-run accuracy and precision were both less than 20% at the lower limit of quantification (LLOQ) spike level. The LLOQ was 0.027 µg/mL which compared well with some values but was also orders of magnitude better than others reported in the literature. The percent recovery was 91.5% at the LLOQ spike level. The DLLME technique was applied in human plasma samples from patients who were on treatment with EFV. The human plasma samples gave concentrations of EFV ranging between 0.14-1.00 µg/mL with three samples out of seven showing concentrations that fell within or close to the recommended therapeutic range.
Subject(s)
Alkynes/blood , Benzoxazines/blood , Cyclopropanes/blood , Gas Chromatography-Mass Spectrometry/methods , Liquid Phase Microextraction/methods , Reverse Transcriptase Inhibitors/blood , Alkynes/chemistry , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/chemistry , Benzoxazines/chemistry , Cyclopropanes/chemistry , Humans , Limit of Detection , Metronidazole/blood , Metronidazole/chemistry , Molecular StructureABSTRACT
OBJECTIVES: To investigate the associations of plasma lamivudine (3TC), abacavir (ABC), emtricitabine (FTC) and tenofovir (TFV) concentrations with cognitive function in a cohort of treated people with HIV (PWH). METHODS: Pharmacokinetics (PK) and cognitive function (Cogstate, six domains) data were obtained from PWH recruited in the POPPY study on either 3TC/ABC or FTC/tenofovir disoproxil fumarate (TDF)-containing regimens. Association between PK parameters (AUC0-24: area under the concentration-time curve over 24 hours, Cmax: maximum concentration and Ctrough: trough concentration) and cognitive scores (standardized into z-scores) were evaluated using rank regression adjusting for potential confounders. RESULTS: Median (IQR) global cognitive z-scores in the 83 PWH on 3TC/ABC and 471 PWH on FTC/TDF were 0.14 (-0.27, 0.38) and 0.09 (-0.28, 0.42), respectively. Higher 3TC AUC0-24 and Ctrough were associated with better global z-scores [rho = 0.29 (p = 0.02) and 0.27 (p = 0.04), respectively], whereas higher 3TC Cmax was associated with poorer z-scores [rho = -0.31 (p<0.01)], independently of ABC concentrations. Associations of ABC PK parameters with global and domain z-scores were non-significant after adjustment for confounders and 3TC concentrations (all p's>0.05). None of the FTC and TFV PK parameters were associated with global or domain cognitive scores. CONCLUSIONS: Whilst we found no evidence of either detrimental or beneficial effects of ABC, FTC and TFV plasma exposure on cognitive function of PWH, higher plasma 3TC exposures were generally associated with better cognitive performance although higher peak concentrations were associated with poorer performance.
Subject(s)
Anti-HIV Agents/blood , Cognition/drug effects , HIV Infections/drug therapy , Reverse Transcriptase Inhibitors/blood , AIDS Dementia Complex/blood , AIDS Dementia Complex/drug therapy , AIDS Dementia Complex/prevention & control , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Cross-Sectional Studies , Drug Therapy, Combination , Female , HIV Infections/blood , HIV Infections/psychology , Humans , Male , Mental Status and Dementia Tests , Middle Aged , Reverse Transcriptase Inhibitors/pharmacology , Reverse Transcriptase Inhibitors/therapeutic use , Socioeconomic Factors , Viral LoadABSTRACT
Cytochrome P450 (CYP) is involved in the metabolism of nevirapine (NVP); especially, CYP2B6 has been known to be one of the main enzymes involved in NVP metabolism. The objective of this study was to investigate the effects of CYP2B6 variants on plasma concentrations of NVP by a systematic review and meta-analysis. A search for qualifying studies published until April 2020 was conducted using the EMBASE, PubMed, and Web of Science databases. The mean difference (MD) and 95% confidence intervals (CIs) were calculated. Data analysis was performed using R Studio (version 3.6) and Review Manager (version 5.3). In total, data from six studies involving 634 patients were analyzed in the systematic review and five studies in the meta-analysis. We found that carriers of the CYP2B6 516TT genotype had a 2.18 µg/mL higher NVP concentration than did the GG or GT (95% CI 1.28-3.08). In the respective comparisons of the three genotypes, it was found that the MD was 1.87 µg/mL between the TT and GT groups, 2.53 µg/mL between TT and GG, and 0.60 µg/mL between GT and GG. This meta-analysis confirmed that CYP2B6 polymorphisms was associated with plasma NVP concentrations. Therefore, CYP2B6 genotyping may be useful to predict the responses to NVP.
Subject(s)
Cytochrome P-450 CYP2B6/genetics , Nevirapine/blood , Polymorphism, Genetic , Reverse Transcriptase Inhibitors/blood , HIV Infections/drug therapy , Humans , Nevirapine/therapeutic use , Reverse Transcriptase Inhibitors/therapeutic useABSTRACT
: Associations between markers of liver and renal dysfunction and nucleotide reverse transcriptase inhibitor plasma exposure are ill-defined. As part of a large cohort study (Pharmacokinetic and Clinical Observations in People over Fifty), we analysed associations between alanine aminotransferase and estimated glomerular filtration rate results in people living with HIV on tenofovir disoproxil fumarate, emtricitabine, abacavir and lamivudine. While we found no associations between nucleotide reverse transcriptase inhibitor concentrations and alanine aminotransferase, lower estimated glomerular filtration rate values were associated with greater tenofovir, emtricitabine and lamivudine exposure, whereas abacavir showed no associations.
Subject(s)
Emtricitabine/blood , HIV Infections/drug therapy , Kidney/metabolism , Lamivudine/blood , Liver/metabolism , Nucleotides/blood , Reverse Transcriptase Inhibitors/blood , Anti-HIV Agents/adverse effects , Anti-HIV Agents/blood , Cohort Studies , Cross-Sectional Studies , Drug Combinations , Emtricitabine/adverse effects , Emtricitabine/therapeutic use , HIV Infections/complications , Humans , Lamivudine/adverse effects , Lamivudine/therapeutic use , Nucleotides/adverse effects , Nucleotides/therapeutic use , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/therapeutic use , Treatment Outcome , Viral LoadABSTRACT
Doravirine is a novel nonnucleoside reverse transcriptase inhibitor indicated for the treatment of HIV type 1 infection. A subset of people living with HIV receives methadone for the treatment of opioid addiction. The current study (NCT02715700) was an open-label, multiple-dose, drug interaction study in participants on a methadone maintenance program to investigate potential drug-drug interactions between doravirine and methadone. Participants received a stable methadone maintenance dose of 20 to 180 mg once daily for 14 days prior to day 1 and remained on their maintenance dose over days 1 through 7. On days 2 through 6, an oral dose of doravirine 100 mg was coadministered. For doravirine and methadone pharmacokinetic analysis, blood samples were collected before dosing through 24 hours after dosing. Fourteen participants were enrolled; all participants completed the study. For R-methadone, geometric least squares mean ratios (90% confidence intervals) for dose-normalized area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration ([methadone + doravirine]/methadone alone) were 0.95 (0.90-1.01), 0.95 (0.88-1.03), and 0.98 (0.93-1.03), respectively. For doravirine, based on a comparison with historical data, modest decreases in area under the plasma concentration-time curve from time zero to 24 hours, plasma concentration at 24 hours, and maximum plasma concentration were observed after coadministration of doravirine and methadone; geometric least squares mean ratios ([methadone + doravirine]/doravirine alone [90% confidence intervals]) were 0.74 (0.61-0.90), 0.80 (0.63-1.03), and 0.76 (0.63-0.91), respectively. Coadministration of doravirine and methadone was generally well tolerated. No serious adverse events occurred, and there were no discontinuations. In conclusion, coadministration of methadone and doravirine did not have a clinically meaningful effect on the pharmacokinetic profile of either agent.
Subject(s)
HIV Infections/drug therapy , Methadone/pharmacokinetics , Opioid-Related Disorders/drug therapy , Pyridones/pharmacokinetics , Triazoles/pharmacokinetics , Adult , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/blood , Analgesics, Opioid/pharmacokinetics , Analgesics, Opioid/pharmacology , Drug Administration Schedule , Drug Interactions/physiology , Drug Therapy, Combination/statistics & numerical data , Female , Humans , Male , Methadone/administration & dosage , Methadone/blood , Methadone/pharmacology , Middle Aged , Outcome Assessment, Health Care , Pyridones/administration & dosage , Pyridones/blood , Pyridones/pharmacology , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacology , Triazoles/administration & dosage , Triazoles/blood , Triazoles/pharmacologyABSTRACT
BACKGROUND: Effective combination antiretroviral therapy (cART) has tremendously reduced HIV-associated morbidity, mortality and mother-to-child transmission. However, the benefits of cART are threatened by comorbidities, adverse drug reactions and virus resistance to existing treatment regimens. One of the most occurring comorbidities is cytomegalovirus (CMV) infection. OBJECTIVES: To investigate the effects of cART on the occurrence of CMV infection among pregnant women. METHODS: Using a cross-sectional study design, 175 HIV-infected pregnant women were recruited, and data were obtained from their clinical records. Blood samples were collected for host DNA, CMV DNA and plasma efavirenz (EFV) measurement. CMV DNA was measured using real-time polymerase chain reaction (PCR). CYP2B6 c.516G>T and CYP2B6 c.983T>C single nucleotide polymorphisms were characterised using PCR/restriction fragment length polymorphism and TaqMan assays, respectively. Plasma EFV concentrations were determined using high-performance liquid chromatography. RESULTS: There was an inverse association between plasma EFV concentration and CMV DNA. Participants with lower plasma EFV concentrations were significantly (p<0.001) more likely to be CMV DNA positive than those with higher plasma concentrations. This result is also supported by the observation that carriers of CYP2B6 poor-metaboliser genotypes (CYP2B6 c.516T/T and CYP2B6 c.983T/C) were less likely to be positive for CMV DNA. Furthermore, poor metabolism as denoted by CYP2B6 c.516T/T and CYP2B6 c.983T/C genotypes was significantly associated with lower CMV viral load. CONCLUSIONS: HIV treatment disrupts the balance between host and co-infecting microbes. Reduced or subtherapeutic levels of antiretroviral drugs, which could be exacerbated by genetic polymorphisms in drug metabolism genes and non-adherence, predispose infected individuals to an increased risk of CMV infection in pregnancy.
Subject(s)
AIDS-Related Opportunistic Infections/etiology , Benzoxazines/pharmacokinetics , Coinfection/etiology , Cytomegalovirus Infections/etiology , Pregnancy Complications, Infectious/etiology , Reverse Transcriptase Inhibitors/pharmacokinetics , AIDS-Related Opportunistic Infections/blood , AIDS-Related Opportunistic Infections/diagnosis , AIDS-Related Opportunistic Infections/prevention & control , Adult , Alkynes , Benzoxazines/blood , Benzoxazines/therapeutic use , Coinfection/blood , Coinfection/diagnosis , Coinfection/prevention & control , Cross-Sectional Studies , Cyclopropanes , Cytomegalovirus Infections/blood , Cytomegalovirus Infections/diagnosis , Cytomegalovirus Infections/prevention & control , Female , Humans , Pregnancy , Pregnancy Complications, Infectious/blood , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/prevention & control , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/therapeutic use , Risk FactorsABSTRACT
BACKGROUND: Efavirenz primary metabolism is catalysed by CYP2B6 with minor involvement of CYP2A6. Subsequently, phase I metabolites are conjugated by UGT2B7, and constitutive androstane receptor (CAR) has been shown to transcriptionally regulate many relevant enzymes and transporters. Several polymorphisms occurring in the genes coding for these proteins have been shown to impact efavirenz pharmacokinetics in some but not all studies. OBJECTIVES: A meta-analysis was performed to assess the overall effect of CYP2B6 rs3745274, CYP2A6 (rs28399454, rs8192726 and rs28399433), UGT2B7 (rs28365062 and rs7439366) and NR1I3 (rs2307424 and rs3003596) polymorphisms on mid-dose efavirenz plasma concentrations. METHODS: Following a literature review, pharmacokinetic parameters were compiled and a meta-analysis for these variants was performed using Review Manager and OpenMetaAnalyst. A total of 28 studies were included. RESULTS: Unsurprisingly, the analysis confirmed that individuals homozygous for the T allele for CYP2B6 rs3745274 had significantly higher efavirenz concentrations than those homozygous for the G allele [weighted standard mean difference (WSMD)â=â2.98; 95% CI 2.19-3.76; Pâ<â0.00001]. A subgroup analysis confirmed ethnic differences in frequency but with a similar effect size in each ethnic group (Pâ=â0.96). Associations with CYP2A6 and UGT2B7 variants were not statistically significant, but T homozygosity for CAR rs2307424 was associated with significantly lower efavirenz concentrations than in C homozygotes (WSMDâ=â-0.32; 95% CI -0.59 to -0.06; Pâ=â0.02). CONCLUSIONS: This meta-analysis provides the overall effect size for the impact of CYP2B6 rs3745274 and NR1I3 rs2307424 on efavirenz pharmacokinetics. The analysis also indicates that some previous associations were not significant when interrogated across studies.
Subject(s)
ATPases Associated with Diverse Cellular Activities/genetics , Benzoxazines/blood , Cytochrome P-450 CYP2A6/genetics , Cytochrome P-450 CYP2B6/genetics , Glucuronosyltransferase/genetics , Metalloendopeptidases/genetics , Reverse Transcriptase Inhibitors/blood , Alkynes , Anti-HIV Agents/blood , Anti-HIV Agents/pharmacokinetics , Benzoxazines/pharmacokinetics , Constitutive Androstane Receptor , Cyclopropanes , Genetic Variation , HIV Infections/drug therapy , HIV Infections/ethnology , Humans , Polymorphism, Single Nucleotide , Reverse Transcriptase Inhibitors/pharmacokineticsABSTRACT
As the HIV epidemic continues to contribute to global morbidity and mortality, the prevalence of HIV-associated neurological disorders (HAND) also continues to be a major concern in infected individuals, despite the widespread use of combination antiretroviral therapy. Therefore, current antiretroviral drugs should be able to reach therapeutic levels in the brain for the treatment of HAND. The brain distribution of the next-generation non-nucleoside reverse transcriptase inhibitor, rilpivirine (RPV) was investigated in healthy female Sprague-Dawley (SD) rats. The presented study involves the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to estimate the concentrations of RPV in plasma and brain homogenate samples. The use of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) provided regional spatial distribution of RPV in brain tissue sections. The localization of RPV was found to be relatively high in the hypothalamus, thalamus and corpus callosum, brain regions known to be associated with neurodegeneration during HAND (including the cerebral cortex). This study has shown that RPV has an excellent blood-brain barrier penetrability. Thus, in combination with other antiretroviral drugs, better central nervous system (CNS) protection against HAND can possibly be achieved.
Subject(s)
Brain/metabolism , HIV Infections/complications , Neurocognitive Disorders/etiology , Rilpivirine/therapeutic use , Animals , Blood-Brain Barrier/metabolism , Chromatography, Liquid , Female , HIV Infections/drug therapy , Humans , Neurocognitive Disorders/virology , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/pharmacokinetics , Reverse Transcriptase Inhibitors/therapeutic use , Rilpivirine/analysis , Rilpivirine/blood , Rilpivirine/pharmacokinetics , Tandem Mass SpectrometryABSTRACT
Absorption, distribution, metabolism and elimination of doravirine (MK-1439), a novel non-nucleoside reverse transcriptase inhibitor, were investigated. Two clinical trials were conducted in healthy subjects: an oral single dose [14 C]doravirine (350 mg, â¼200 µCi) trial (n = 6) and an intravenous (IV) single-dose doravirine (100 µg) trial (n = 12). In vitro metabolism, protein binding, apparent permeability and P-glycoprotein (P-gp) transport studies were conducted to complement the clinical trials. Following oral [14 C]doravirine administration, all of the administered dose was recovered. The absorbed dose was eliminated primarily via metabolism. An oxidative metabolite (M9) was the predominant metabolite in excreta and was the primary circulating metabolite (12.9% of circulating radioactivity). Following IV administration, doravirine clearance and volume of distribution were 3.73 L/h (95% confidence intervals (CI) 3.09, 4.49) and 60.5 L (95% CI 53.7, 68.4), respectively. In vitro, doravirine is not highly bound to plasma proteins (unbound fraction 0.24) and has good passive permeability. The metabolite M9 was generated by cytochrome P450 3A (CYP3A)4/5-mediated oxidation. Doravirine was a P-gp substrate but P-gp efflux is not expected to play a significant role in limiting doravirine absorption or to be involved in the elimination of doravirine. In conclusion, doravirine is a low clearance drug, primarily eliminated by CYP3A-mediated metabolism.
Subject(s)
Absorption, Physiological , Pyridones/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Triazoles/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Intravenous , Adult , Humans , Male , Metabolome/drug effects , Middle Aged , Pyridones/blood , Pyridones/chemistry , Pyridones/urine , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/urine , Tissue Distribution , Triazoles/blood , Triazoles/chemistry , Triazoles/urine , Young AdultABSTRACT
We compared efavirenz pharmacokinetic (PK) parameters in children with tuberculosis (TB)/human immunodeficiency virus (HIV) coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children 3 to 14 years old with HIV infection, with and without TB, were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization-recommended antituberculosis drug dosages were used in the coinfected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon rank-sum test and within group by signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age Z score, and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz peak concentration (Cmax), concentration at 12 h (C12h), Cmin, and total area under the curve from time 0 to 24 h (AUC0-24h) values were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz C12h, Cmin, and AUC0-24h values were lower in TB/HIV-coinfected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC0-24h was higher on than in patients off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children. (The study was registered with ClinicalTrials.gov under registration number NCT01704144.).
Subject(s)
Anti-Retroviral Agents/blood , Antitubercular Agents/therapeutic use , Benzoxazines/blood , HIV Infections/drug therapy , Isoniazid/therapeutic use , Reverse Transcriptase Inhibitors/blood , Rifampin/therapeutic use , Tuberculosis, Pulmonary/drug therapy , Adolescent , Alkynes , Anti-Retroviral Agents/therapeutic use , Benzoxazines/pharmacokinetics , Benzoxazines/therapeutic use , Child , Child, Preschool , Chromatography, Liquid , Coinfection/drug therapy , Cyclopropanes , Drug Interactions , Female , Humans , Male , Reverse Transcriptase Inhibitors/therapeutic use , Tandem Mass SpectrometryABSTRACT
Efavirenz is a highly effective HIV-1 antiretroviral; however, it is also frequently associated with neuropsychiatric adverse events (NPAE) that include abnormal dreams, sleep disturbances, nervousness, anxiety, depression, and dizziness. The incidence of NPAEs upon initiation of treatment with efavirenz-containing medications is high, exceeding 50% in most studies. Although the NPAEs tend to decrease after the first month in many patients, they persist for long periods of time in others. Efavirenz-based treatment is generally well-tolerated in children, although some experience persistent concentration problems, as well as sleep disturbances, psychotic reactions, and seizures. In an effort to link basic with clinical research, parameters associated with efavirenz brain exposure are discussed, and factors that increase efavirenz levels are explored in depth as they are expected to contribute to NPAE risk. These include the role of modifiable and nonmodifiable risk factors such as diet, weight, and drug-drug interactions and sex, age, and ethnicity/pharmacogenetics. In addition to NPAEs, this review explores what is known about antiretroviral (ARV) drugs being used for recreational purposes. Although multiple ARV drugs are covered, special attention is devoted to efavirenz given that the majority of reports of NPAEs and illicit use of ARV drugs concern efavirenz. The evolving molecular mechanistic basis of NPAEs and abuse of efavirenz point to a complex and polymodal receptor pharmacology. Animal studies to date primarily point to a serotonergic mechanism of action. Recently emerging associations between HIV-associated neurocognitive disorder and efavirenz use, and possible contributions of the mitochondrial-immune-inflammatory-redox cascade are explored in the context of the signaling mechanisms that appear to be involved.
Subject(s)
Anti-HIV Agents/adverse effects , Benzoxazines/adverse effects , Neurotoxicity Syndromes , Reverse Transcriptase Inhibitors/adverse effects , Alkynes , Animals , Anti-HIV Agents/blood , Anti-HIV Agents/pharmacokinetics , Benzoxazines/blood , Benzoxazines/pharmacokinetics , Cyclopropanes , HIV Infections/drug therapy , Humans , Illicit Drugs/adverse effects , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/pharmacokineticsABSTRACT
Background: In the ANRS 165 DARULIGHT study (NCT02384967) carried out in HIV-infected patients, the use of a darunavir/ritonavir-containing regimen with a switch to a reduced dose of darunavir maintained virological efficacy (≤50 copies/mL) for 48 weeks with a good safety profile. Objectives: To assess the total and unbound blood plasma pharmacokinetics of darunavir and associated antiretrovirals, and their penetration into semen before and after dose reduction. Patients and methods: Patients receiving a darunavir/ritonavir (800/100 mg q24h)-containing regimen for >6 months with plasma HIV-RNA ≤50 copies/mL for >12 months were switched to 400/100 mg darunavir/ritonavir q24h at week 0. A 24 h intensive pharmacokinetic blood sampling and a trough seminal sampling were performed before (week 0) and after (week 12) dose reduction. Individual pharmacokinetic parameter estimates were obtained using non-linear mixed-effect modelling for darunavir/ritonavir in blood plasma and used to test for bioequivalence, whereas darunavir/ritonavir in seminal plasma and NRTIs were analysed using a non-compartmental approach. Results and conclusions: Fifteen patients completed the intensive pharmacokinetic analysis. There was no significant decrease in total and unbound darunavir blood plasma exposure despite a 50% decrease in darunavir daily dose from 800 to 400 mg (AUC0-24 = 65â¯563 versus 52â¯518 ng·h/mL; P = 0.25). A decrease in apparent oral clearance (CL/F) of both darunavir and ritonavir at week 12 suggests a modification of the initial darunavir/ritonavir daily dose balance (800/100 to 400/100 mg), in favour of a reduced inducer effect of darunavir on cytochrome P450 and efflux transporters compared with the standard dose.
Subject(s)
Darunavir/administration & dosage , Darunavir/pharmacokinetics , HIV Infections/drug therapy , Ritonavir/administration & dosage , Ritonavir/pharmacokinetics , Adult , Darunavir/blood , Drug Therapy, Combination , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/pharmacokinetics , Humans , Male , Middle Aged , Plasma/chemistry , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/pharmacokinetics , Ritonavir/blood , Semen/chemistry , Therapeutic EquivalencyABSTRACT
Nucleoside reverse transcriptase inhibitors (NRTIs) require intracellular phosphorylation to active triphosphate (TP) nucleotide metabolites before they can inhibit the HIV reverse transcriptase. However, monitoring these pharmacologically active TP metabolites is challenging due to their instability and their low concentrations at the pg/ml levels in blood and tissues. The combination of lamivudine (3TC) and abacavir (ABC) is one of the first lines for HIV therapy. Therefore, a sensitive, selective, accurate, and precise LC-MS/MS method was developed and validated for the simultaneous quantification of 3TC- and ABC-TP metabolites in mouse blood and tissues. Calibration curves were linear over the range of 10-100,000â¯pg/ml for 3TC-TP and 4-40,000â¯pg/ml for carbovir-TP (CBV-TP; phosphorylated metabolite of ABC). This corresponds to 2.1-21,322 fmol/106 cells for 3TC-TP and 0.8-8000â¯fmol/106 cells for CBV-TP. Accuracy and precision were less than 15% for all quality control sample (QCs), and absolute extraction recovery of were >65% for 3TC-TP and >90% for CBV-TP. The method was optimized to ensure stability of TP samples and standards during sample collection, preparation, analysis, and storage conditions. This method has enhanced sensitivity and requires smaller amounts of blood and tissue samples compared to previous LC-MS/MS methods for 3TC- and CBV-TP quantification. The developed method was successfully applied to characterize the pharmacokinetic profile of TP metabolites in mouse peripheral blood mononuclear cells (PBMCs), spleen, lymph nodes, and liver cells. In addition, another direct, simple, and high-throughput method for the quantification of TP standards was developed and used for the analysis of stability samples.
Subject(s)
Dideoxynucleosides/blood , Lamivudine/blood , Polyphosphates/blood , Animals , Anti-HIV Agents/blood , Chromatography, Liquid/methods , Humans , Leukocytes, Mononuclear/metabolism , Male , Mice , Mice, Inbred BALB C , Reverse Transcriptase Inhibitors/blood , Tandem Mass Spectrometry/methodsABSTRACT
Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) widely used in the treatment of human immunodeficiency virus type 1 (HIV-1) and is the first-choice NNRTI during pregnancy. NVP shows a sex dimorphic profile in humans with sex differences in bioavailability, biotransformation and toxicity. In this study, sex differences in NVP metabolism and inhibition of NVP metabolism by the antidepressant nortriptyline (NT) were evaluated using rats as experimental animals. NVP was administered orally to male and female rats and sex differences in plasma levels and pharmacokinetic parameters were analysed. NVP plasma levels were higher in female compared with male rats, and pharmacokinetic parameters such as maximum plasma concentration (Cmax), time to Cmax (Tmax), half-life (t1/2) and area under the plasma concentration-time curve from the time of dosing to the last measurable concentration (AUClast) showed ca. 4-, 5-, 7- and 22-fold higher values in female rats. In vitro experiments carried out with hepatic microsomes confirmed slower NVP metabolism in female rats, with a maximum velocity (Vmax) 2-fold lower than in male hepatic microsomes. The major metabolite in both sexes was 12-hydroxynevirapine (12-OH-NVP), with the Vmax for this metabolite being 15-fold lower in female compared with male rat hepatic microsomes. Inhibition of NVP metabolism by NT was similar in both sexes, with statistically non-significant differences in 50% inhibitory concentration (IC50) values. In summary, NVP is metabolised more slowly in female compared with male rats, but the inhibitory effect of NT is similar in both sexes.
Subject(s)
Nevirapine/pharmacokinetics , Nortriptyline/pharmacokinetics , Animals , Antidepressive Agents, Tricyclic/pharmacokinetics , Drug Interactions , Female , Male , Microsomes, Liver/drug effects , Nevirapine/blood , Rats, Wistar , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/pharmacokinetics , Sex FactorsABSTRACT
Sparse tissue sampling with intensive plasma sampling creates a unique data analysis problem in determining drug exposure in clinically relevant tissues. Tissue exposure may govern drug efficacy, as many drugs exert their actions in tissues. We compared tissue area-under-the-curve (AUC) generated from bootstrapped noncompartmental analysis (NCA) methods and compartmental nonlinear mixed effect (NLME) modeling. A model of observed data after single-dose tenofovir disoproxil fumarate was used to simulate plasma and tissue concentrations for two destructive tissue sampling schemes. Two groups of 100 data sets with densely-sampled plasma and one tissue sample per individual were created. The bootstrapped NCA (SAS 9.3) used a trapezoidal method to calculate geometric mean tissue AUC per dataset. For NLME, individual post hoc estimates of tissue AUC were determined, and the geometric mean from each dataset calculated. Median normalized prediction error (NPE) and absolute normalized prediction error (ANPE) were calculated for each method from the true values of the modeled concentrations. Both methods produced similar tissue AUC estimates close to true values. Although the NLME-generated AUC estimates had larger NPEs, it had smaller ANPEs. Overall, NLME NPEs showed AUC under-prediction but improved precision and fewer outliers. The bootstrapped NCA method produced more accurate estimates but with some NPEs > 100%. In general, NLME is preferred, as it accommodates less intensive tissue sampling with reasonable results, and provides simulation capabilities for optimizing tissue distribution. However, if the main goal is an accurate AUC for the studied scenario, and relatively intense tissue sampling is feasible, the NCA bootstrap method is a reasonable, and potentially less time-intensive solution.
Subject(s)
Computer Simulation , Models, Biological , Nonlinear Dynamics , Reverse Transcriptase Inhibitors/pharmacokinetics , Tenofovir/pharmacokinetics , Area Under Curve , Computer Simulation/statistics & numerical data , Female , Humans , Male , Reverse Transcriptase Inhibitors/blood , Tenofovir/blood , Tissue Distribution/drug effects , Tissue Distribution/physiologyABSTRACT
Biallelic mutations of three prime repair exonuclease 1 (TREX1) cause the lupus-like disease Aicardi-Goutières syndrome in which accumulation of a yet unknown endogenous DNA substrate of TREX1 triggers a cyclic GMP-AMP synthase-dependent type I IFN response and systemic autoimmunity. Products of reverse transcription originating from endogenous retroelements have been suggested to be a major substrate for TREX1, and reverse transcriptase inhibitors (RTIs) were proposed as a therapeutic option in autoimmunity ensuing from defects of TREX1. In this study, we treated Trex1-/- mice with RTIs. The serum RTI levels reached were sufficient to block retrotransposition of endogenous retroelements. However, the treatment did not reduce the spontaneous type I IFN response and did not ameliorate lethal inflammation. Furthermore, long interspersed nuclear elements 1 retrotransposition was not enhanced in the absence of Trex1. Our data do not support the concept of retroelement-derived cDNA as key triggers of systemic autoimmunity in Trex1-deficient humans and mice and motivate the continuing search for the pathogenic IFN-inducing Trex1 substrate.
Subject(s)
Autoimmunity , Exodeoxyribonucleases/metabolism , Phosphoproteins/metabolism , Reverse Transcriptase Inhibitors/blood , Animals , Autoimmune Diseases of the Nervous System/immunology , DNA, Complementary , Exodeoxyribonucleases/deficiency , Exodeoxyribonucleases/genetics , HeLa Cells , Humans , Inflammation , Interferon Type I/biosynthesis , Interferon Type I/immunology , Mice , Mutation , Nervous System Malformations/immunology , Phosphoproteins/deficiency , Phosphoproteins/genetics , Retroelements , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/therapeutic use , Reverse TranscriptionABSTRACT
HIV infection is often associated with liver failure, which alters the pharmacokinetics of many drugs. In this study we investigated whether acute liver failure (ALF) altered the pharmacokinetics of the first-line anti-HIV agent zidovudine (AZT), a P-gp/BCRP substrate, in rats. ALF was induced in rats by injecting thioacetamide (TAA, 300 mg·kg-1·d-1, ip) for 2 days. On the second day after the last injection of TAA, the pharmacokinetics of AZT was investigated following both oral (20 mg/kg) and intravenous (10 mg/kg) administration. ALF significantly increased the plasma concentrations of AZT after both oral and intravenous doses of AZT, but without affecting the urinary excretion of AZT. AZT metabolism was studied in rat hepatic microsomes in vitro, which revealed that hepatic UGT2B7 was the main enzyme responsible for the formation of AZT O-glucuronide (GAZT); ALF markedly impaired AZT metabolism in hepatic microsomes, which was associated with the significantly decreased hepatic UGT2B7 expression. Intestinal absorption of AZT was further studied in rats via in situ single-pass intestinal perfusion. Intestinal P-gp function and intestinal integrity were assessed with rhodamine 123 and FD-70, respectively. We found that ALF significantly downregulated intestinal P-gp expression, and had a smaller effect on intestinal BCRP. Further studies showed that ALF significantly increased the intestinal absorption of both rhodamine 123 and AZT without altering intestinal integrity, thus confirming an impairment of intestinal P-gp function. In conclusion, ALF significantly increases the oral plasma exposure of AZT in rats, a result partly attributed to the impaired function and expression of hepatic UGT2B7 and intestinal P-gp.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Glucuronosyltransferase/metabolism , Jejunum/metabolism , Liver Failure, Acute/enzymology , Liver/enzymology , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/pharmacokinetics , Zidovudine/administration & dosage , Zidovudine/pharmacokinetics , Administration, Intravenous , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Intestinal Absorption , Male , Microsomes, Liver/enzymology , Rats, Sprague-Dawley , Renal Elimination , Reverse Transcriptase Inhibitors/blood , Thioacetamide , Zidovudine/bloodABSTRACT
BACKGROUND: Doravirine is a potent, once-daily, non-nucleoside reverse transcriptase inhibitor with a distinct resistance profile in Phase III development for the treatment of HIV-1. As doravirine may be administered to women and the elderly, we investigated the effect of gender and age in doravirine pharmacokinetics. METHODS: In this Phase I, open-label, single-period, parallel-group investigation, doravirine 100 mg was administered to 36 healthy subjects in three groups: elderly men (n=12, 65-80 years), elderly women (n=12, 65-80 years) and young women (n=12, 18-50 years). Data for young men (n=6, 18-50 years) from a previous study were included as a comparator. Doravirine plasma pharmacokinetics and safety were assessed. RESULTS: No clinically meaningful effect on pharmacokinetics was observed in association with gender or age. Gender effects were assessed using combined data from elderly and young men versus elderly and young women because the datasets met predefined pooling criteria. The geometric mean ratios (GMRs; women/men [90% CIs]) of doravirine AUC0-∞, Cmax and C24h were 1.20 (1.03, 1.40), 1.42 (1.23, 1.64) and 1.02 (0.84, 1.24), respectively. Age effects were assessed separately in men and women because the datasets did not meet pooling criteria. The AUC0-∞, Cmax, and C24h GMRs (elderly/young) were 0.85 (0.67, 1.10), 0.92 (0.73, 1.16), 0.81 (0.59, 1.11), respectively for men and 0.97 (0.79, 1.19), 1.18 (0.98, 1.42), 0.94 (0.72, 1.21), respectively, for women. Doravirine was well-tolerated throughout the trial. CONCLUSIONS: Neither gender nor age affects the bioavailability of single-dose doravirine 100 mg in healthy subjects, thus supporting administration of doravirine 100 mg in elderly and adult women without dose adjustment.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Pyridones/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Triazoles/pharmacokinetics , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Anti-HIV Agents/blood , Area Under Curve , Biological Availability , Drug Administration Schedule , Fasting/blood , Female , Healthy Volunteers , Humans , Male , Middle Aged , Patient Safety , Pyridones/blood , Reverse Transcriptase Inhibitors/blood , Sex Factors , Triazoles/bloodABSTRACT
INTRODUCTION: Doravirine, a non-nucleoside reverse-transcriptase inhibitor in development for the treatment of patients with human immunodeficiency virus-1 infection, has potential to be used concomitantly in antiretroviral therapy with dolutegravir, an integrase strand transfer inhibitor. The pharmacokinetic interactions between these drugs were therefore assessed. METHODS: Oral formulations of doravirine and dolutegravir were dosed both individually and concomitantly once daily in healthy adults. Twelve subjects (six were male), 23-42 years of age, were enrolled and 11 completed this phase I, open-label, three-period, fixed-sequence study per protocol; one subject was discontinued for a positive cotinine test at admission to period 2. In period 1, dolutegravir 50 mg was administered for 7 days. After a 7-day washout, doravirine 200 mg was dosed for 7 days in period 2, followed (without washout) by both doravirine and dolutegravir simultaneously for 7 days in period 3. Plasma samples were taken to determine dolutegravir and doravirine concentrations. RESULTS: The steady-state concentration 24 h post-dose (C24) of dolutegravir was not substantially altered by co-administration of doravirine multiple doses; area under the plasma concentration-time curve from dosing to 24 h post-dose (AUC0-24), maximum concentration (C max), and C24 geometric mean ratios were 1.36, 1.43, and 1.27, respectively. The pharmacokinetics of doravirine was not affected by multiple doses of dolutegravir (geometric mean ratios: 1.00, 0.98, and 1.06 for AUC0-24, C24, and C max, respectively). Both drugs were generally well tolerated. CONCLUSION: The results of this study demonstrate that concomitant administration of doravirine and dolutegravir in healthy subjects causes no clinically significant alteration in the pharmacokinetic and safety profiles of the two drugs, thereby supporting further evaluation of co-administration of these agents for human immunodeficiency virus-1 treatment.