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OBJECTIVES: Understanding the influence of fetal and maternal genetics on prenatal drug exposure could potentially improve benefit-risk evaluation. In this study, we investigated the impact of two functional polymorphisms in CYP2B6 on prenatal exposure to efavirenz. METHODS: Dried blood spot (DBS) samples were collected from HIV-positive pregnant women (nâ =â 112) and their newborns (nâ =â 107) at delivery. They were genotyped for single nucleotide polymorphisms in CYP2B6. Efavirenz was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Significant correlations were observed in efavirenz concentration between maternal and newborn (râ =â 0.46, R2â =â 0.21, Pâ <â 0.001), and maternal and cord (râ =â 0.83, R2â =â 0.68, Pâ <â 0.001) samples. Median (interquartile range) newborn plasma-to-maternal plasma and cord-to-maternal plasma ratios were 0.85 (0.03-3.49) and 0.78 (0.23-1.96), respectively. Newborn efavirenz concentration in DBS varied significantly based on composite maternal CYP2B6 genotype: fast (CYP2B6 516GG and 983TT, nâ =â 26), 747â ng/ml (602-1060); intermediate (CYP2B6 516GT or 983TC nâ =â 50), 1177 ng/ml (898-1765); and slow (CYP2B6 516GT and 983TC or 516TT or 983CC, nâ =â 14), 3094 ng/ml (2126-3812). Composite newborn CYP2B6 genotype was, however, not significantly associated with prenatal exposure. Efavirenz concentration in newborn stratified as fast (nâ =â 25), intermediate (nâ =â 36), and slow metabolizers (nâ =â 19) from prenatal exposure was 999.7â (774-1285), 1240 (709-1984), and 1792 ng/ml (1201-3188), respectively. CONCLUSION: The clinical relevance of the observed influence of maternal genetics on prenatal efavirenz exposure requires further investigation.
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AIMS: Long-acting cabotegravir and rilpivirine have been approved to manage HIV in adults, but data regarding safe use in pregnancy are limited. Physiologically-based pharmacokinetic (PBPK) modelling was used to simulate the approved dosing regimens in pregnancy and explore if Ctrough was maintained above cabotegravir and rilpivirine target concentrations (664 and 50 ng/mL, respectively). METHODS: An adult PBPK model was validated using clinical data of cabotegravir and rilpivirine in nonpregnant adults. This was modified by incorporating pregnancy-induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Twelve weeks' disposition of monthly and bimonthly dosing of long-acting cabotegravir and rilpivirine was simulated at different trimesters and foetal exposure was also estimated. RESULTS: Predicted Ctrough at week 12 for monthly long-acting cabotegravir was above 664 ng/mL throughout pregnancy, but below the target in 0.5% of the pregnant population in the third trimester with bimonthly long-acting cabotegravir. Predicted Ctrough at week 12 for monthly and bimonthly long-acting rilpivirine was below 50 ng/mL in at least 40% and over 90% of the pregnant population, respectively, throughout pregnancy. Predicted medians (range) of cord-to-maternal blood ratios were 1.71 (range, 1.55-1.79) for cabotegravir and 0.88 (0.78-0.93) for rilpivirine between weeks 38 and 40. CONCLUSIONS: Model predictions suggest that monthly long-acting cabotegravir could maintain antiviral efficacy throughout pregnancy, but that bimonthly administration may require careful clinical evaluation. Both monthly and bimonthly long-acting rilpivirine may not adequately maintain antiviral efficacy in pregnancy.
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BACKGROUND: We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV who started on antiretroviral therapy during pregnancy and with high viremia during post-partum. METHODS: This was a cross-sectional study of women with viral loads greater than 1000 copies/ml who were at least 6 weeks postpartum. Sanger sequencing was used to detect resistant mutations, as well as host genotyping, and efavirenz resistance was compared among the metabolizer genotypes. RESULTS: Over the course of one year (July 2017-July 2018), 322 women were screened, with 110 (34.2%) having viral loads of 1000 copies/ml and 62 having whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. Efavirenz resistance according to metabolizer genotype was; 47% in slow, 34% in extensive and 28% in intermediate metabolizers, but the difference was not statistically significant due to the small sample size. CONCLUSIONS: There was no statistically significant difference in EFV resistance between EFV metabolizer genotypes in women who started antiretroviral therapy during pregnancy and had high viremia in the postpartum period. However, a numerical trend was discovered, which calls for confirmation in a large, well-designed, statistically powered study.
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Fármacos Anti-HIV , Infecções por HIV , Gravidez , Humanos , Feminino , Citocromo P-450 CYP2B6/genética , Fármacos Anti-HIV/uso terapêutico , Estudos Transversais , Uganda/epidemiologia , Viremia/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Genótipo , Benzoxazinas/uso terapêutico , Período Pós-PartoRESUMO
Lack of predictive preclinical models is a key contributor to the steep attrition rate in drug development. Successful clinical translation may be higher for new chemical entities or existing approved drugs reformulated for long-acting (LA) administration if preclinical studies designed to identify any new uncertainties are predictive of human exposure and response. In this review, we present an overview of standard preclinical assessments deployed for LA formulations and delivery systems, using human immunodeficiency virus LA therapeutics preclinical development as a paradigm. Key progress in the preclinical development of novel LA antiretrovirals formulations and delivery systems are summarized, including bispecific broadly neutralizing monoclonal antibody and small molecule technologies for codelivery of multiple drugs with disparate solubility properties. There are new opportunities to take advantage of recent developments in tissue engineering and 3-dimensional in vitro modeling to advance preclinical modeling of anti-infective activity, developmental and reproductive toxicity assessment, and to apply quantitative modeling and simulation strategies. These developments are likely to drive the progression of more LA anti-infective drugs and multipurpose technologies into clinical development in the coming years.
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Anti-Infecciosos , Infecções por HIV , Humanos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Composição de Medicamentos , Desenvolvimento de Medicamentos , Simulação por ComputadorRESUMO
Long-acting agents hold significant promise for treating and preventing common illnesses, including infections. Pharmacokinetic and safety data during pregnancy and lactation are often unavailable for new drugs; these data are vital to facilitate optimal drug use by pregnant and lactating women and women who may conceive. In this commentary, we summarize the circumstances in which pregnant and lactating women are likely to use and benefit from long-acting agents. We focus on long-acting formulations of small molecules (rather than biologics such as monoclonal antibodies) and on several infections of global importance (human immunodeficiency virus, tuberculosis, malaria, and hepatitis C). We discuss pregnancy pharmacokinetic/pharmacodynamic and potential safety and efficacy considerations pertaining to the use of long-acting agents in pregnancy and lactation. Finally, we summarize existing preclinical and pregnancy pharmacokinetic data that are available (or expected in the near future) for several agents that are under development or approved, and how key research gaps may be addressed.
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Hepatite C , Lactação , Gravidez , Feminino , Humanos , Aleitamento Materno , Hepacivirus , Anticorpos MonoclonaisRESUMO
BACKGROUND: Dolutegravir is currently the preferred component of first-line antiretroviral therapy. To facilitate clinical pharmacology studies in key populations, quantitative analytical methods compatible with microsampling and adaptable to resource-limited settings are desirable. The authors developed and validated a liquid chromatography-ultraviolet detection method to quantify dolutegravir in dried blood spots (DBS). METHODS: Calibration standards and quality control samples were prepared by spotting 50 µL of dolutegravir-spiked whole blood on each circle of DBS cards. Three spots (two 6-mm punches/spot) were extracted with methanol. Chromatographic separation was achieved with gradient elution of acetonitrile/potassium phosphate monobasic buffer (pH 5) on a reverse-phase C18 column (flow rate, 1 mL/min) using pioglitazone as the internal standard. UV detection was performed at 260 nm. In the clinical pharmacokinetic study, DBS from finger prick was collected from participants (n = 10) at 8 time points over 12 hours postdosing, with paired plasma at 1 and 12 hours. The method was used to quantify dolutegravir, estimating pharmacokinetic parameters. Agreement between DBS and plasma concentrations was evaluated using linearity and Bland-Altman plots. RESULTS: The method was validated over the concentration range of 0.4-10 mcg/mL, accuracy was 102.4%-114.8%, and precision was 3.4%-14.7%. The mean recovery was 42.3% (%CV: 8.3). The mean (±SD) dolutegravir concentration in DBS was 37.5% (±3.8%) lower than that in the plasma. DBS-derived and measured plasma concentrations showed strong correlation with linearity (R2 = 0.9804) and Bland-Altman plots. Means (%CV) of area under curve, Cmax, and C24 from the DBS-derived plasma concentration were 37.8 (23.2) mcg·h/mL, 2.7 (24.7) mcg/mL, and 1.34 (31.6) mcg/mL, respectively. CONCLUSIONS: The application of this simple, accurate, and precise method will expand opportunities for clinical assessment of dolutegravir in resource-limited settings.
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Compostos Heterocíclicos com 3 Anéis , Oxazinas , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco/métodos , Humanos , Piperazinas , Piridonas , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Strategies to support adherence are constrained by the lack of tools to objectively monitor medication intake in low-resource settings. Pharmacologic measures are objective, but pharmacy refill data is more accessible and cost-efficient. This study compared short-term and long-term efavirenz (EFV) drug levels with pharmacy refill adherence data (PRA) and evaluated their ability to predict viral suppression among people living with HIV in Nigeria. METHODS: Paired hair and dried blood spot (DBS) samples were obtained from 91 adults living with HIV receiving 600 mg EFV-based antiretroviral therapy (ART) and EFV concentrations were measured via validated methods using liquid-chromatography-mass-spectrometry. PRA was estimated from pharmacy records, based on the number of days a patient collected medication before or after the scheduled pick-up date. PRA was categorized into ≤ 74%, 75-94% and ≥ 95%, defined as poor, medium and high adherence, respectively. HIV viral loads closest to the hair sampling time (within 6 months) were also abstracted. Receiver Operating Characteristics (ROC) curve analyses compared the ability of adherence metrics to predict viral suppression. RESULTS: Based on PRA, 81% of participants had high adherence while 11% and 8% had medium and poor adherence, respectively. The median (IQR) EFV concentrations were 6.85 ng/mg (4.56-10.93) for hair and 1495.6 ng/ml (1050.7-2365.8) for DBS. Of the three measures of adherence, hair EFV concentration had the highest Area Under Curve (AUC) to predict viral suppression. Correlations between EFV concentrations in DBS and hair with PRA were positive (r = 0.12, P = 0.27 and r = 0.21, P = 0.05, respectively) but not strong. CONCLUSIONS: EFV concentrations in hair were the strongest predictor of viral suppression and only weakly correlated with pharmacy refill adherence data in Nigeria. This study suggests that resource-limited settings may benefit from objective adherence metrics to monitor and support adherence.
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Fármacos Anti-HIV , Infecções por HIV , Farmácia , Adulto , Alcinos , Fármacos Anti-HIV/análise , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas , Ciclopropanos , Infecções por HIV/tratamento farmacológico , Cabelo/química , Humanos , NigériaRESUMO
BACKGROUND: Coadministration of artemether-lumefantrine and efavirenz has been shown to result in significant interactions. The influence of functional genetic polymorphisms in selected CYPs on the magnitude of this interaction was investigated in pregnant and nonpregnant adults. METHOD: A standard 3-day regimen of artemether-lumefantrine was administered to each patient on steady-state efavirenz-based antiretroviral therapy (ART). Pharmacokinetic parameters were obtained from intensive plasma concentration-time data. Genotyping data were tested for compliance with Hardy-Weinberg equilibrium by Chi-square test. Linear regressions, Mann-Whitney U-test or Kruskal-Wallis tests were conducted to examine the association of lumefantrine plasma level with CYP2B6 c.516G>T, NR1I3 152c-1089T>C, CYP2B6 c.983T>C, CYP3A5*3 and CYP3A4*22. RESULTS: Among a total of 69 malaria-HIV coinfected patients (34 nonpregnant and 35 pregnant), median (interquartile range) age was 33 (27-36.5) years and body weight was 59.5 (50-67.5) kg. In nonpregnant group, CYP2B6 c.516G>T was significantly associated with lower log Cday 7 of lumefantrine using multivariate linear regressions (ß = -0.239; P = 0.013). In 59% of women with CYP2B6 c.516T, Cday 7 of lumefantrine was below the target of 280 ng/mL compared to 47% in the noncarriers. CYP2B6 c.983T>C significantly associated with higher log Cday 7 of desbutyl lumefantrine in both pregnant (ß = 0.383; P = 0.033) and nonpregnant (ß = 0.395; P = 0.023) groups. Composite genotypes for both CYP2B6 Single-nucleotide polymorphisms strongly associated with lumefantrine plasma concentration. An associative trend between lumefantrine pharmacokinetics and NR1I3 152c-1089T>C genotypes indicated that 70% of the Cday 7 of lumefantrine in those with NR1I3 152c-1089TT genotype was below 280 ng/mL compared to 53% in those with NR1I3 152c-1089CC or CT genotype. CONCLUSION: The findings revealed that the efavirenz-lumefantrine interaction was accentuated in the group with CYP2B6 c.516T, c.983C and NR1I3 152c-1089T alleles. This warrants further investigations of other drug-drug interactions for optimising dosing in genetically defined subgroups, particularly during drug development.
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Alcinos/administração & dosagem , Combinação Arteméter e Lumefantrina/administração & dosagem , Benzoxazinas/administração & dosagem , Ciclopropanos/administração & dosagem , Sistema Enzimático do Citocromo P-450/genética , Infecções por HIV/tratamento farmacológico , Malária/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/genética , Adulto , Alcinos/farmacocinética , Combinação Arteméter e Lumefantrina/farmacocinética , Benzoxazinas/farmacocinética , Estudos de Casos e Controles , Receptor Constitutivo de Androstano , Ciclopropanos/farmacocinética , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP3A/genética , Feminino , Técnicas de Genotipagem , Infecções por HIV/genética , Humanos , Malária/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Resultado do TratamentoRESUMO
There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes, were administered a complete treatment dose of 3 days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted, and the plasma concentrations of artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry. Pharmacokinetic parameters of artemether-lumefantrine and its metabolites in HIV-infected patients on nevirapine were compared to those in the absence of nevirapine in HIV-negative volunteers. Overall, nevirapine reduced exposure to artemether and desbutyl-lumefantrine by 39 and 34%, respectively. These reductions were significantly greater in GG versus TT subjects for artemether (ratio of geometric mean [90% confidence interval]: 0.42 [0.29 to 0.61] versus 0.81 [0.51 to 1.28]) and for desbutyl-lumefantrine (0.56 [0.43 to 0.74] versus 0.75 [0.56 to 1.00]). On the contrary, it increased exposure to dihydroartemisinin and lumefantrine by 47 and 30%, respectively. These increases were significantly higher in TT versus GG subjects for dihydroartemisinin (1.67 [1.20 to 2.34] versus 1.25 [0.88 to 1.78]) and for lumefantrine (1.51 [1.20 to 1.90] versus 1.08 [0.82 to 1.42]). This study underscores the importance of incorporating pharmacogenetics into all drug-drug interaction studies with potential for genetic polymorphisms to influence drug disposition.
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Citocromo P-450 CYP2B6/genética , Polimorfismo Genético/genética , Artemeter/farmacologia , Combinação Arteméter e Lumefantrina/farmacologia , Genótipo , HIV/genética , Nevirapina/farmacologiaRESUMO
AIMS: Lopinavir (LPV) is not a first-line regimen. According to recent WHO data, LPV usage in low- and middle-income countries accounted for approximately 52% of the adult and 23% of the paediatric protease inhibitor market in 2017. Since LPV is a substrate for the SLCO1B1 (OATP1B1) transporter, the aim of this study was to assess the impact of SLCO1B1 polymorphisms (rs11045819, rs4149032 and rs4149056) on LPV trough plasma concentrations (Ctrough ) in Serbian patients. METHODS: Plasma samples from 104 HIV/AIDS Caucasians were collected. LPV Ctrough was quantified using liquid-chromatography-mass spectrometry. Genotyping was carried out using real-time-PCR-based allelic discrimination. One-way analysis of variance, t test and linear regression were used for data analysis. RESULTS: The overall mean (SD) LPV Ctrough was 5885 ± 2755 ng/mL. Significant differences were between patients with different rs11045819 genotypes: CC (LPV median Ctrough = 6072 ng/mL, interquartile range (IQR) = 4318-7617 ng/mL), CA (LPV median Ctrough = 4987 ng/mL, IQR = 4300-6295 ng/mL) and AA (LPV median Ctrough = 3648 ng/mL, IQR = 1949-4072 ng/mL) (P = .005). Significant differences were also observed according to rs4149032 genotype: CC (LPV median Ctrough = 6027 ng/mL, IQR =4548-8250 ng/mL), CT (LPV median Ctrough = 5553 ng/mL, IQR = 4300-6888 ng/mL) and TT (LPV median Ctrough = 4408 ng/mL, IQR = 3361-5233 ng/mL) (P = .007). For rs4149056 a statistically significant difference between T-homozygotes (LPV median Ctrough = 5434 ng/mL, IQR = 3855-6830 ng/mL), heterozygotes (LPV median Ctrough = 6707 ng/mL, IQR = 5088-8063 ng/mL) and C-homozygotes (LPV median Ctrough = 13906 ng/mL, IQR = 12946-14866 ng/mL) was observed (P = .002). In multivariate regression analysis, only the SLCO1B1 rs4149056 polymorphism was independently associated with higher LPV Ctrough (ß = 2834.5 [1442-4226.9] ng/mL [P = .001]). CONCLUSIONS: Our results demonstrate a statistically significant influence of the SLCO1B1 rs4149056 polymorphism on higher LPV Ctrough in Caucasian HIV/AIDS patients.
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Infecções por HIV , Inibidores da Protease de HIV , Adulto , Criança , Genótipo , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado , Lopinavir/uso terapêutico , Polimorfismo Genético , RitonavirRESUMO
Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.
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Antibióticos Antituberculose/farmacocinética , Hidrolases de Éster Carboxílico/genética , Polimorfismo de Nucleotídeo Único , Rifampina/análogos & derivados , Tuberculose Pulmonar/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antituberculose/uso terapêutico , Antituberculosos/uso terapêutico , Receptor Constitutivo de Androstano , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Receptor de Pregnano X/genética , Receptores Citoplasmáticos e Nucleares/genética , Rifampina/farmacocinética , Rifampina/uso terapêutico , Adulto JovemRESUMO
AIMS: In this study the influence of first-line antimalarial drug artemether-lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV-infected Nigerian patients. METHODS: This was a two-period, single sequence crossover study. In stage 1, 150 HIV-infected patients receiving nevirapine-based antiretroviral regimens were enrolled and genotyped for seven SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorized as poor, intermediate and extensive metabolizers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether-lumefantrine treatment with nevirapine, and intensive pharmacokinetic sampling was conducted on day 3. RESULTS: No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80-1.25 no-effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3400 ng ml-1 minimum effective concentration increased from 10% without artemether-lumefantrine (all extensive metabolizers) to 21% with artemether-lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolizers). CONCLUSIONS: This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolizers when nevirapine is co-administered with artemether-lumefantrine.
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Antimaláricos/farmacocinética , Combinação Arteméter e Lumefantrina/farmacocinética , Infecções por HIV/tratamento farmacológico , Malária/tratamento farmacológico , Nevirapina/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Antimaláricos/administração & dosagem , Combinação Arteméter e Lumefantrina/administração & dosagem , Estudos Cross-Over , Citocromo P-450 CYP2B6/genética , Interações Medicamentosas , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Humanos , Malária/complicações , Masculino , Pessoa de Meia-Idade , Nevirapina/administração & dosagem , Nigéria , Polimorfismo de Nucleotídeo Único , Inibidores da Transcriptase Reversa/administração & dosagemRESUMO
Artemether-lumefantrine is often coadministered with efavirenz-based antiretroviral therapy for malaria treatment in HIV-infected women during pregnancy. Previous studies showed changes in lumefantrine pharmacokinetics due to interaction with efavirenz in nonpregnant adults. The influence of pregnancy on this interaction has not been reported. This pharmacokinetic study involved 35 pregnant and 34 nonpregnant HIV-malaria-coinfected women receiving efavirenz-based antiretroviral therapy and was conducted in four health facilities in Nigeria. Participants received a 3-day standard regimen of artemether-lumefantrine for malaria treatment, and intensive pharmacokinetic sampling was conducted from 0.5 to 96 h after the last dose. Plasma efavirenz, lumefantrine, and desbutyl-lumefantrine were quantified using validated assays, and pharmacokinetic parameters were derived using noncompartmental analysis. The median middose plasma concentrations of efavirenz were significantly lower in pregnant women (n = 32) than in nonpregnant women (n = 32) at 1,820 ng/ml (interquartile range, 1,300 to 2,610 ng/ml) versus 2,760 ng/ml (interquartile range, 2,020 to 5,640 ng/ml), respectively (P = 0.006). The lumefantrine area under the concentration-time curve from 0 to 96 h was significantly higher in pregnant women (n = 27) at 155,832 ng · h/ml (interquartile range, 102,400 to 214,011 ng · h/ml) than nonpregnant women at 90,594 ng · h/ml (interquartile range, 58,869 to 149,775 ng · h/ml) (P = 0.03). A similar trend was observed for the lumefantrine concentration at 12 h after the last dose of lumefantrine, which was 2,870 ng/ml (interquartile range, 2,180 to 4,880 ng/ml) versus 2,080 ng/ml (interquartile range, 1,190 to 2,970 ng/ml) in pregnant and nonpregnant women, respectively (P = 0.02). The lumefantrine-to-desbutyl-lumefantrine ratio also tended to be lower in pregnant women than in nonpregnant women (P = 0.076). Overall, pregnancy tempered the extent of efavirenz-lumefantrine interactions, resulting in increased lumefantrine exposure. However, any consideration of dosage adjustment for artemether-lumefantrine to enhance exposure in this population needs to be based on data from a prospective study with safety and efficacy endpoints.
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Benzoxazinas/farmacocinética , Lumefantrina/farmacocinética , Adulto , Alcinos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Benzoxazinas/uso terapêutico , Ciclopropanos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lumefantrina/uso terapêutico , Malária/tratamento farmacológico , GravidezRESUMO
OBJECTIVES: Lack of data on the pharmacokinetics of efavirenz in pregnant women at the 400 mg reduced dose currently prevents universal roll-out. Population pharmacokinetic modelling was used to explore pharmacokinetic endpoints at 200, 400 and 600 mg daily doses in pregnant women stratified by CYP2B6 metabolic status. METHODS: The analysis was based on 252 plasma efavirenz concentrations from 77 pregnant women (77 sparse, 175 intensive) who received antiretroviral regimens containing 600 mg of efavirenz. The model was developed using NONMEM®. The effect of genetics was investigated and concentration-time courses at steady-state were simulated for individuals (n = 1000 each) classified as CYP2B6 slow, intermediate and fast metabolizers at 200, 400 and 600 mg daily doses. RESULTS: At a 400 mg reduced dose, predicted mean (90% CI) mid-dose efavirenz concentration (C12) was 2.24 µg/mL (0.89-4.18) in pregnant women classified as slow metabolizers, compared with 0.87 µg/mL (0.34-1.64) in intermediate metabolizers and 0.78 µg/mL (0.30-1.47) in fast metabolizers. C12 was below the 0.47 µg/mL threshold determined within the ENCORE 1 trial in 10% at 400 mg, 4.6% at 600 mg and 3.4% with genotype-guided dosing. The 4.0 µg/mL toxicity threshold was exceeded in 4.6% at 400 mg, 13.5% at 600 mg and 5.2% with genotype-guided dosing. CONCLUSIONS: These data provide context for the ongoing debate about reduction in efavirenz dose to 400 mg during pregnancy and should be interpreted alongside the lower toxicity expected with the lower dose. Additional research is required to investigate genotype-guided dose reduction in pregnant women.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Indutores do Citocromo P-450 CYP2B6/farmacocinética , Citocromo P-450 CYP2B6/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Adolescente , Adulto , Alcinos , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , População Negra , Ciclopropanos , Indutores do Citocromo P-450 CYP2B6/administração & dosagem , Indutores do Citocromo P-450 CYP2B6/uso terapêutico , Feminino , Infecções por HIV/prevenção & controle , Humanos , Nigéria , Gravidez , Adulto JovemRESUMO
Background: Breast milk transfer of first-line ART from mother to infant is not fully understood. Objectives: To determine the concentrations of lamivudine, emtricitabine and tenofovir in maternal blood, breast milk and infant blood from breastfeeding mother-infant pairs. Methods: Intensive pharmacokinetic sampling of maternal dried blood spots (DBS), dried breast milk spots (DBMS) and infant DBS from 30 Ugandan and 29 Nigerian mothers receiving first-line ART and their infants was conducted. DBS and DBMS were collected pre-dose and at 5-6 timepoints up to 12 h following observed dosing. Infant DBS were sampled twice during this period. Lamivudine, emtricitabine and tenofovir were quantified using LC-MS/MS, with non-compartmental analysis to calculate key pharmacokinetic parameters. Results: Peak concentrations in breast milk from women taking lamivudine and emtricitabine occurred later than in plasma (4-8 h compared with 2 h for lamivudine and 2-4 h for emtricitabine). Consequently, the milk-to-plasma (M:P) ratio of lamivudine taken once daily was 0.95 (0.82-1.15) for AUC0-12, whereas for AUC12-20 this was 3.04 (2.87-4.16). Lamivudine was detectable in 36% (14/39) of infants [median 17.7 (16.3-22.7) ng/mL]. For 200 mg of emtricitabine once daily, the median M:P ratio was 3.01 (2.06-3.38). Three infants (19%) had measurable emtricitabine [median 18.5 (17.6-20.8) ng/mL]. For 300 mg of tenofovir once daily, the median M:P ratio was 0.015 (0-0.03) and no infant had measurable tenofovir concentrations. Conclusions: Emtricitabine and lamivudine accumulate in breast milk and were detected in breastfeeding infants. In contrast, tenofovir penetrates the breast milk to a small degree, but is undetectable in breastfeeding infants.
Assuntos
Fármacos Anti-HIV/farmacocinética , Aleitamento Materno , Emtricitabina/farmacocinética , Lamivudina/farmacocinética , Leite Humano/química , Plasma/química , Tenofovir/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Cromatografia Líquida , Estudos de Coortes , Emtricitabina/administração & dosagem , Feminino , Humanos , Lactente , Lamivudina/administração & dosagem , Masculino , Mães , Nigéria , Espectrometria de Massas em Tandem , Tenofovir/administração & dosagem , Uganda , Adulto JovemRESUMO
OBJECTIVES: Previous studies on nevirapine pharmacokinetics during pregnancy reported contradictory findings. METHODS: The magnitude of pregnancy-induced changes in nevirapine pharmacokinetics was investigated in a genotype-guided study preceded by a pharmacogenetic association study of six genes involved in its disposition. RESULTS: CYP2B6 516 G>T and 983 T>C were associated independently with plasma nevirapine concentrations in pregnant (n=110) and postpartum (n=122) women and were used for stratification. NR1I3 540C>T and P450 oxidoreductase 1508C>T were associated with lower and higher plasma concentrations in pregnant and postpartum women, respectively. In the intensive pharmacokinetic phase, apparent clearance (CL/F) was higher in pregnant (n=31) than postpartum (n=28) women (P=0.022) and AUC0-12, Cmax and Cmin were significantly lower. When stratified on the basis of composite CYP2B6 516 G>T and 983 T>C genotypes, CL/F was similar between pregnant (n=6) and postpartum (n=9) women with no variant alleles, but Cmin was below target (3400 ng/ml) in most patients in both groups. In women with one variant allele, clearance was 40.6% higher (P=0.0009) and Cmin was below target in 58% (11/19) of pregnant and 0% (0/10) of postpartum women. Similarly, clearance was 51.7% higher (P=0.008) in pregnant compared with postpartum women with two variant alleles. Cmin was below target in 50% (3/6) of pregnant and 0% (0/10) of postpartum women. CONCLUSION: Nevirapine exposure is significantly reduced during pregnancy. The pharmacodynamic consequences in patients at risk of suboptimal exposure and potential dose optimization strategies warrant further investigation.
Assuntos
Fármacos Anti-HIV/farmacocinética , Biomarcadores/metabolismo , Citocromo P-450 CYP2B6/genética , Nevirapina/farmacocinética , Polimorfismo Genético/genética , Adulto , Receptor Constitutivo de Androstano , Feminino , Genótipo , Humanos , Período Pós-Parto , Gravidez , Distribuição TecidualRESUMO
AIMS: Using a model-based approach, the efavirenz steady-state pharmacokinetics in African children is characterized, quantifying demographic and genotypic effects on the drug's disposition. Simulations are also conducted allowing prediction of optimized doses of efavirenz in this population. METHODS: We modelled the steady-state population pharmacokinetics of efavirenz in Ugandan and Zambian children using nonlinear mixed-effects modelling. Individual mid-dose efavirenz concentrations were derived and simulations explored genotype-based dose optimization strategies. RESULTS: A two-compartment model with absorption through transit compartments well described 2086 concentration-time points in 169 children. The combined effect of single nucleotide polymorphisms (SNPs) 516G>T and 983T>C explained 44.5% and 14.7% of the variability in efavirenz clearance and bioavailability, respectively. The detected frequencies of composite CYP2B6 genotype were 0.33 for 516GG|983TT, 0.35 for 516GT|983TT, 0.06 for 516GG|983TC, 0.18 for 516TT|983TT, 0.07 516GT|983TC and 0.01 for 516GG|983CC. The corresponding estimated clearance rates were 6.94, 4.90, 3.93, 1.92, 1.36, and 0.74 l h(-1) for a 15.4 kg child and median (95% CI) observed mid-dose concentrations 1.55 (0.51-2.94), 2.20 (0.97-4.40), 2.03 (1.19-4.53), 7.55 (2.40-14.74), 7.79 (3.66-24.59) and 18.22 (11.84-22.76) mg l(-1) , respectively. Simulations showed that wild-type individuals had exposures at the bottom of therapeutic range, while slower metabolizers were overexposed. CONCLUSIONS: Dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C.
Assuntos
Benzoxazinas/farmacocinética , Citocromo P-450 CYP2B6/genética , Modelos Biológicos , Inibidores da Transcriptase Reversa/farmacocinética , Adolescente , Alcinos , Benzoxazinas/administração & dosagem , População Negra/genética , Criança , Pré-Escolar , Simulação por Computador , Ciclopropanos , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Masculino , Dinâmica não Linear , Polimorfismo de Nucleotídeo Único , Inibidores da Transcriptase Reversa/administração & dosagem , Fatores de Tempo , Uganda , ZâmbiaRESUMO
BACKGROUND: The antiretroviral drug efavirenz is widely used during breastfeeding. Evaluating its safety requires an understanding of its breast milk pharmacokinetics, level of breastfed infants' exposure, and potential influence of polymorphisms in drug disposition genes. METHODS: For this observational study, we investigated plasma and breast milk pharmacokinetics of efavirenz and breastfed infants' exposure in human immunodeficiency virus positive nursing mothers and their breastfed infants. We also evaluated potential variability due to genetic polymorphisms in CYP2B6, NR1I3, CYP2A6, ABCB1, ABCB5, and ABCG2. RESULTS: CYP2B6 516G>T was independently associated with efavirenz concentrations in maternal plasma, breast milk, and infant plasma (n = 134). When stratified based on CYP2B6 516G>T (n = 29 ; 11 GG, 10 GT and 8 TT), efavirenz pharmacokinetic parameters in plasma and breast milk differed significantly between patient groups. The median time-averaged milk-to-plasma concentration ratio was 1.10 (range: 0.57-1.71). The estimated maximum infant efavirenz dose from breast milk was 809 µg/kg/day (215-2760) and pediatric dose weight-adjusted exposure index was 4.05% (1.08-13.8). Infant plasma concentrations did not change significantly during the dosing interval, 157 ng/mL (28.6-1360) in pooled analysis and 315 ng/mL (108-1360) in CYP2B6 516TT group. Infant plasma concentrations were highest up to 8 days of age at 1590 ng/mL (190-4631) and decreased by about 90% in the age stratum day 9 to 3 months. No efavirenz related toxicity was reported. CONCLUSIONS: Most breastfed infants are exposed to <10% of the weight-adjusted therapeutic pediatric dose, the safety threshold for exposure to maternal drugs from breast milk.
Assuntos
Fármacos Anti-HIV/análise , Fármacos Anti-HIV/farmacocinética , Benzoxazinas/análise , Benzoxazinas/farmacocinética , Infecções por HIV/genética , Leite Humano/química , Adolescente , Adulto , Alcinos , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/sangue , Benzoxazinas/uso terapêutico , Aleitamento Materno , Receptor Constitutivo de Androstano , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Leite Humano/metabolismo , Farmacogenética , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
OBJECTIVES: Antiretroviral pharmacokinetics is defined by numerous factors affecting absorption, distribution, metabolism and elimination. Biological processes underpinning drug distribution are only partially characterized and multiple genetic factors generate cumulative or antagonistic interactions, which complicates the implementation of pharmacogenetic markers. The aim of this study was to assess the degree to which heredity influences pharmacokinetics through the quantification of the relative genetic contribution (rGC) for key antiretrovirals. METHODS: A total of 407 patients receiving lopinavir/ritonavir, atazanavir/ritonavir, atazanavir, efavirenz, nevirapine, etravirine, maraviroc, tenofovir or raltegravir were included. Intra-patient variability (SDw) and inter-patient (SDb) variability were measured in patients with plasma concentrations available from more than two visits. The rGC was calculated using the following equation: 1â-â(1â/âF) where Fâ=âSDb(2)â/âSDw(2). RESULTS: Mean (95% CI) rGC was calculated to be 0.81 (0.72-0.88) for efavirenz, 0.74 (0.61-0.84) for nevirapine, 0.67 (0.49-0.78) for etravirine, 0.65 (0.41-0.79) for tenofovir, 0.59 (0.38-0.74) for atazanavir, 0.47 (0.27-0.60) for atazanavir/ritonavir, 0.36 (0.01-0.48) for maraviroc, 0.15 (0.01-0.44) for lopinavir/ritonavir and 0 (0-0.33) for raltegravir. CONCLUSIONS: The rank order for genetic contribution to variability in plasma concentrations for the study drugs was efavirenz > nevirapine > etravirine > tenofovir > atazanavir > atazanavir/ritonavir > maraviroc > lopinavir/ritonavir > raltegravir, indicating that class-specific differences exist. The rGC strategy represents a useful tool to rationalize future investigations as drugs with higher rGC scores may represent better candidates for pharmacogenetic-pharmacokinetic studies.
Assuntos
Antirretrovirais/farmacocinética , Farmacogenética/métodos , Plasma/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirretrovirais/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVES: The validation and clinical application of an LC-MS/MS method for the quantification of nevirapine in dried blood spots (DBS) and dried breast-milk spots (DBMS) are presented. METHODS: DBS and DBMS were prepared from 50 and 30 µL of nevirapine-spiked whole blood and human breast milk, respectively. Chromatographic separation was achieved on a reverse-phase C18 column with 0.1% formic acid in water/acetonitrile using a solvent gradient programme at a flow rate of 400 µL/min, and detection was by a TSQ Quantum Access triple quadrupole mass spectrometer. The clinical application was evaluated in HIV-positive nursing mothers and their breastfed infants. RESULTS: The assay was validated over the concentration range 50-10,000 ng/mL. Accuracy ranged from 93.3% to 113.4% and precision ranged from 1.9% to 12.0%. The mean (percentage coefficient of variation) recovery of nevirapine from DBS and DBMS was ≥ 70.7% (≤ 8.2) and the matrix effect was ≤ 1.04 (≤ 6.1). Nevirapine was stable in DBS and DBMS for ≥ 15 months at room temperature and -80°C. Mean (SD) AUC0-12, Cmax and Cmin in maternal plasma versus breast milk were 57,808 ng · h/mL (24,315) versus 55,817 ng · h/mL (22,368), 6140 ng/mL (2605) versus 5231 ng/mL (2215) and 4334 ng/mL (1880) versus 4342 ng/mL (2245), respectively. The milk-to-plasma concentration ratio over the dosing interval was 0.94 (0.15). Infant plasma concentrations 2 and 8 h after maternal dosing were 580.6 ng/mL (464.7-1607) and 584.1 ng/mL (381.5-1570), respectively. CONCLUSIONS: These methods further extend opportunities for conducting clinical pharmacokinetic studies in nursing mother-infant pairs, especially in resource-limited settings.