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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: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. METHODS: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100â mg OD (baseline); PK2 300/100â mg OD with rifampicin 600â mg; PK3 300/100â mg BID with rifampicin 600â mg OD; PK4 300/100â mg BID with rifampicin 1200â mg OD. Dolutegravir 50â mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014â mg/L. RESULTS: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, while 65% of PK2 Ctau were below the limit of quantification (0.03â mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia. CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.
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Developing long-acting products and formulations for infectious diseases is a nontrivial undertaking that is frequently classified as high risk and low reward by the pharmaceutical industry. The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) was founded in 2015 with the support of the National Institutes of Health to encourage, promote, and accelerate the development of such products. Assessment methodology for any new proposal brought to this group is part of a framework-the LEAP Process-that includes a landscape analysis of what is currently available in the public domain. This is followed by in silico modeling and simulation offered as a service to the relevant scientific community. A variety of preclinical and clinical outcome metrics are applied to each new agent as part of a continuous feedback loop to improve product characteristics. This allows us to catalog knowledge gaps and barriers that can be addressed by engaged stakeholders. Results are communicated in scientific articles, reviews, and position papers. This undertaking serves to de-risk discovery, development, and implementation by bridging the gaps between academic, regulatory, and industrial investigators, and by engaging those in the community who will be the eventual users of these medicines. The LEAP Process has supported formulations now approved for human immunodeficiency virus, as well as products in clinical and preclinical development for tuberculosis and hepatitis viruses B and C.
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Infecciones por VIH , Tuberculosis , Estados Unidos , Humanos , Antirretrovirales/uso terapéutico , Industria Farmacéutica , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , National Institutes of Health (U.S.)RESUMEN
BACKGROUND: Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART. OBJECTIVES: To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48â weeks. PATIENTS AND METHODS: Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6â weeks or darunavir-based ART with a run-in of 2â weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48â weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI. RESULTS: At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99-1.37); levonorgestrel: 1.16 (0.97-1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69-3.28); levonorgestrel: 1.89 (1.38-2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel. CONCLUSIONS: Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART.
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Infecciones por VIH , Levonorgestrel , Femenino , Humanos , Darunavir/efectos adversos , Levonorgestrel/efectos adversos , Levonorgestrel/farmacocinética , Rilpivirina/efectos adversos , Ritonavir , Progestinas , Infecciones por VIH/tratamiento farmacológico , AnticonceptivosRESUMEN
OBJECTIVES: The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug-drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CLint.app. ) and CYP gene expression. METHODS: In vitro CYP-mediated CLint.app. of levonorgestrel was quantified using a recombinant human CYP (rhCYP) enzyme system. A primary human hepatocyte model of drug metabolism was used to assess the effects of dolutegravir on (1) levonorgestrel CLint.app. , using liquid chromatography-tandem mass spectrometry, and (2) the expression of specific CYP enzymes, using quantitative real-time polymerase chain reaction. RESULTS: Levonorgestrel clearance was mediated by multiple rhCYPs, including rhCYP3A4. Under control conditions, levonorgestrel CLint.app. was 22.4 ± 5.0 µL/min/106 hepatocytes. Incubation with 43.1 nM of unbound dolutegravir elevated levonorgestrel CLint.app. to 31.4 ± 7.8 µL/min/106 hepatocytes (P = 0.168), while 142.23 nM increased levonorgestrel CLint.app. to 37.0 ± 2.9 µL/min/106 hepatocytes (P = 0.012). Unbound dolutegravir ≥ 431 nM induced expression of CYP3A4 (≥ two-fold) in a dose-dependent manner, while 1.44 µM of unbound dolutegravir induced CYP2B6 expression 2.2 ± 0.3-fold (P = 0.0004). CONCLUSIONS: In summary, this in vitro study suggests that dolutegravir has the potential to increase hepatic clearance of levonorgestrel by inducing both CYP3A and non-CYP3A enzymes. The observed in vitro dolutegravir-levonorgestrel drug-drug interaction should be further examined in clinical studies.
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Infecciones por VIH , Levonorgestrel , Citocromo P-450 CYP3A , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Oxazinas , Piperazinas , PiridonasRESUMEN
AIMS: The impact of ageing on antiretroviral pharmacokinetics remains uncertain, leading to missing dosing recommendations for elderly people living with human immunodeficiency virus (HIV: PLWH). The objective of this study was to investigate whether ageing leads to clinically relevant pharmacokinetic changes of antiretrovirals that would support a dose adjustment based on the age of the treated PLWH. METHODS: Plasma concentrations for 10 first-line antiretrovirals were obtained in PLWH ≥55 years, participating in the Swiss HIV Cohort Study, and used to proof the predictive performance of our physiologically based pharmacokinetic (PBPK) model. The verified PBPK model predicted the continuous effect of ageing on HIV drug pharmacokinetics across adulthood (20-99 years). The impact of ethnicity on age-related pharmacokinetic changes between whites and other races was statistically analysed. RESULTS: Clinically observed concentration-time profiles of all investigated antiretrovirals were generally within the 95% confidence interval of the PBPK simulations, demonstrating the predictive power of the modelling approach used. The predicted decline in drug clearance drove age-related pharmacokinetic changes of antiretrovirals, resulting in a maximal 70% [95% confidence interval: 40%, 120%] increase in antiretrovirals exposure across adulthood. Peak concentration, time to peak concentration and apparent volume of distribution were predicted to be unaltered by ageing. There was no statistically significant difference of age-related pharmacokinetic changes between studied ethnicities. CONCLUSION: Dose adjustment for antiretrovirals based on the age of male and female PLWH is a priori not necessary in the absence of severe comorbidities considering the large safety margin of the current first-line HIV treatments.
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Infecciones por VIH , Preparaciones Farmacéuticas , Adulto , Anciano , Envejecimiento , Estudios de Cohortes , Simulación por Computador , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Modelos Biológicos , FarmacocinéticaRESUMEN
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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Alquinos/administración & dosificación , Combinación Arteméter y Lumefantrina/administración & dosificación , Benzoxazinas/administración & dosificación , Ciclopropanos/administración & dosificación , Sistema Enzimático del Citocromo P-450/genética , Infecciones por VIH/tratamiento farmacológico , Malaria/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares/genética , Adulto , Alquinos/farmacocinética , Combinación Arteméter y Lumefantrina/farmacocinética , Benzoxazinas/farmacocinética , Estudios de Casos y Controles , Receptor de Androstano Constitutivo , Ciclopropanos/farmacocinética , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP3A/genética , Femenino , Técnicas de Genotipaje , Infecciones por VIH/genética , Humanos , Malaria/genética , Polimorfismo de Nucleótido Simple , Embarazo , Resultado del TratamientoRESUMEN
Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Adenina/análogos & derivados , Alanina , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Leucocitos Mononucleares , Tenofovir/uso terapéuticoRESUMEN
The development of therapeutic agents against SARS-CoV-2/COVID-19 faces numerous barriers and a multidisciplinary approach to evaluating drug efficacy and toxicity is essential. Experimental and preclinical data should be integrated into a comprehensive analysis, where drug potency, the timing of therapy initiation, drug combinations, variability in systemic and local drug exposure and short- and long-term toxicities represent fundamental factors for the rational identification of candidates and prioritization of clinical investigations. Although the identification of SARS-CoV-2 therapeutics is a priority, rigorous and transparent methodologies are crucial to ensure that accelerated research programmes result in high-quality and reproducible findings.
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Anticuerpos Antivirales/efectos de los fármacos , Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Descubrimiento de Drogas/tendencias , Neumonía Viral/tratamiento farmacológico , Animales , Anticuerpos Antivirales/sangre , Antivirales/farmacología , COVID-19 , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Descubrimiento de Drogas/métodos , Humanos , Pandemias , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , SARS-CoV-2RESUMEN
BACKGROUND: Only a few antiretroviral drugs (ARVs) are recommended for use during the neonatal period and there is a need for more to be approved to increase treatment and prophylaxis strategies. Dolutegravir, a selective integrase inhibitor, has potential for treatment of HIV infection and prophylaxis of transmission in neonates. OBJECTIVES: To model the pharmacokinetics of dolutegravir in neonates and to simulate a theoretical optimal dosing regimen. METHODS: The physiologically based pharmacokinetic (PBPK) model was built incorporating the age-related changes observed in neonates. Virtual neonates between 0 and 28 days were simulated. The model was validated against observed clinical data for raltegravir and midazolam in neonates, prior to the prediction of dolutegravir pharmacokinetics. RESULTS: Both raltegravir and midazolam passed the criteria for model qualification, with simulated data within 1.8-fold of clinical data. The qualified model predicted the pharmacokinetics for several multidose regimens of dolutegravir. Regimen 6 involved 5 mg doses with a 48 h interval from Day 1-20, increasing to 5 mg once daily on Week 3, yielding AUC and Ctrough values of 37.2 mg·h/L and 1.3 mg/L, respectively. These exposures are consistent with those observed in paediatric patients receiving dolutegravir. CONCLUSIONS: Dolutegravir pharmacokinetics were successfully simulated in the neonatal PBPK model. The predictions suggest that during the first 3 weeks of life a 5 mg dose administered every 48 h may achieve plasma exposures needed for therapy and prophylaxis.
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Infecciones por VIH , Inhibidores de Integrasa VIH , Niño , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Recién Nacido , Oxazinas , Piperazinas/uso terapéutico , PiridonasRESUMEN
As global health services respond to the coronavirus pandemic, many prescribers are turning to experimental drugs. This review aims to assess the risk of drug-drug interactions in the severely ill COVID-19 patient. Experimental therapies were identified by searching ClinicalTrials.gov for 'COVID-19', '2019-nCoV', '2019 novel coronavirus' and 'SARS-CoV-2'. The last search was performed on 30 June 2020. Herbal medicines, blood-derived products and in vitro studies were excluded. We identified comorbidities by searching PubMed for the MeSH terms 'COVID-19', 'Comorbidity' and 'Epidemiological Factors'. Potential drug-drug interactions were evaluated according to known pharmacokinetics, overlapping toxicities and QT risk. Drug-drug interactions were graded GREEN and YELLOW: no clinically significant interaction; AMBER: caution; RED: serious risk. A total of 2378 records were retrieved from ClinicalTrials.gov, which yielded 249 drugs that met inclusion criteria. Thirteen primary compounds were screened against 512 comedications. A full database of these interactions is available at www.covid19-druginteractions.org. Experimental therapies for COVID-19 present a risk of drug-drug interactions, with lopinavir/ritonavir (10% RED, 41% AMBER; mainly a perpetrator of pharmacokinetic interactions but also risk of QT prolongation particularly when given with concomitant drugs that can prolong QT), chloroquine and hydroxychloroquine (both 7% RED and 27% AMBER, victims of some interactions due to metabolic profile but also perpetrators of QT prolongation) posing the greatest risk. With management, these risks can be mitigated. We have published a drug-drug interaction resource to facilitate medication review for the critically ill patient.
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Antivirales/farmacocinética , Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Interacciones Farmacológicas , Neumonía Viral/tratamiento farmacológico , Terapias en Investigación/efectos adversos , Antivirales/efectos adversos , COVID-19 , Humanos , Pandemias , SARS-CoV-2RESUMEN
BACKGROUND: Cabotegravir and rilpivirine are 2 long-acting (LA) antiretrovirals that can be administered intramuscularly; their interaction with rifampicin, a first-line antituberculosis agent, has not been investigated. The aim of this study was to simulate and predict drug-drug interactions (DDIs) between these LA antiretroviral agents and rifampicin using physiologically based pharmacokinetic (PBPK) modeling. METHODS: The designed PBPK models were qualified (according to European Medicines Agency guidelines) against observed data for oral formulations of cabotegravir, rilpivirine, and rifampicin. Induction potential of rifampicin was also qualified by comparing the DDI between oral cabotegravir and oral rilpivirine with rifampicin. Qualified PBPK models were utilized for pharmacokinetic prediction of DDIs. RESULTS: PBPK models predicted a reduction in both area under the curve (AUC0-28 days) and trough concentration (Ctrough, 28th day) of LA cabotegravir of 41%-46% for the first maintenance dose coadministered with 600 mg once-daily oral rifampicin. Rilpivirine concentrations were predicted to decrease by 82% for both AUC0-28 days and Ctrough, 28th day following the first maintenance dose when coadministered with rifampicin. CONCLUSIONS: The developed PBPK models predicted the theoretical effect of rifampicin on cabotegravir and rilpivirine LA intramuscular formulations. According to these simulations, it is likely that coadministration of rifampicin with these LA formulations will result in subtherapeutic concentrations of both drugs.
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Antirretrovirales/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Piridonas/farmacocinética , Rifampin/farmacocinética , Rilpivirina/farmacocinética , Adolescente , Adulto , Simulación por Computador , Preparaciones de Acción Retardada , Composición de Medicamentos , Interacciones Farmacológicas , Femenino , Infecciones por VIH/virología , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Modelos Teóricos , Adulto JovenRESUMEN
BACKGROUND: We previously demonstrated that etonogestrel concentrations were 82% lower in women using etonogestrel contraceptive implants plus efavirenz-based ART compared with women not receiving ART. OBJECTIVES: To investigate the genetic contribution to this previously observed drug-drug interaction through studying SNPs in genes known to be involved in efavirenz, nevirapine or etonogestrel metabolism in the same group of women. PATIENTS AND METHODS: Here, we present a secondary analysis evaluating SNPs involved in efavirenz, nevirapine and etonogestrel metabolism and associated etonogestrel pharmacokinetics among 57 women, 19 not receiving ART (control group), 19 receiving efavirenz- (600 mg daily) based ART and 19 receiving nevirapine- (200 mg twice daily) based ART. Associations between patient genotype and etonogestrel pharmacokinetic parameters were determined through univariate and multivariate linear regression. This study was registered at clinicaltrials.gov (NCT02082652). RESULTS: Within the control group, CYP2B6 983 T>C was associated with 27% higher etonogestrel Cmax and 28% higher AUC0-24weeks. In the efavirenz group CYP2B6 516 G>T was associated with 43% lower etonogestrel Cmin and 34% lower AUC0-24weeks. For participants receiving nevirapine, NR1I2 63396 C>T was associated with 39% lower etonogestrel Cmin and 37% lower AUC0-24weeks. CONCLUSIONS: This study demonstrates the influence of pharmacogenetics on the extent of drug-drug interactions between etonogestrel and efavirenz- or nevirapine-based ART. Efavirenz plus the etonogestrel contraceptive implant results in a detrimental drug-drug interaction irrespective of patient genetics, which is worsened in women possessing variant alleles for these CYP2B6 SNPs.
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Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/uso terapéutico , Desogestrel/farmacocinética , Nevirapina/uso terapéutico , Adulto , Alquinos , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Interacciones Farmacológicas/genética , Femenino , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Adulto JovenRESUMEN
Despite their high potential for drug-drug interactions (DDI), clinical DDI studies of antiretroviral drugs (ARVs) are often lacking, because the full range of potential interactions cannot feasibly or pragmatically be studied, with some high-risk DDI studies also being ethically difficult to undertake. Thus, a robust method to screen and to predict the likelihood of DDIs is required. We developed a method to predict DDIs based on two parameters: the degree of metabolism by specific enzymes, such as CYP3A, and the strength of an inhibitor or inducer. These parameters were derived from existing studies utilizing paradigm substrates, inducers, and inhibitors of CYP3A to assess the predictive performance of this method by verifying predicted magnitudes of changes in drug exposure against clinical DDI studies involving ARVs. The derived parameters were consistent with the FDA classification of sensitive CYP3A substrates and the strength of CYP3A inhibitors and inducers. Characterized DDI magnitudes (n = 68) between ARVs and comedications were successfully quantified, meaning 53%, 85%, and 98% of the predictions were within 1.25-fold (0.80 to 1.25), 1.5-fold (0.66 to 1.48), and 2-fold (0.66 to 1.94) of the observed clinical data. In addition, the method identifies CYP3A substrates likely to be highly or, conversely, minimally impacted by CYP3A inhibitors or inducers, thus categorizing the magnitude of DDIs. The developed effective and robust method has the potential to support a more rational identification of dose adjustment to overcome DDIs, being particularly relevant in an HIV setting, given the treatment's complexity, high DDI risk, and limited guidance on the management of DDIs.
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Antirretrovirales/uso terapéutico , Inhibidores del Citocromo P-450 CYP3A/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Infecciones por VIH/metabolismo , Humanos , Método de MontecarloRESUMEN
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 , Alquinos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Benzoxazinas/uso terapéutico , Ciclopropanos , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Lumefantrina/uso terapéutico , Malaria/tratamiento farmacológico , EmbarazoRESUMEN
Background: HIV-positive women receiving efavirenz-based ART and levonorgestrel contraceptive implants are at risk of low levonorgestrel exposure and unintended pregnancy. Objectives: To investigate clinically applicable dose-adjustment strategies to overcome the known drug-drug interaction (DDI) between levonorgestrel and efavirenz, using a physiologically based pharmacokinetic (PBPK) modelling-based approach. Methods: A PBPK model was qualified against clinical data to predict levonorgestrel plasma concentrations when standard-dose (150 mg) levonorgestrel implants were administered alone (control group), as well as when standard-dose or increased-dose (300 mg) levonorgestrel implants were coadministered with either 600 or 400 mg of efavirenz. Results: No difference was seen between in vivo clinical and PBPK-model-simulated levonorgestrel plasma concentrations (P > 0.05). Simulated levonorgestrel plasma concentrations were â¼50% lower at 48 weeks post-implant-placement in virtual individuals receiving standard-dose levonorgestrel with either 600 or 400 mg of efavirenz compared with the control group (efavirenz:control geometric mean ratio = 0.42 and 0.49, respectively). Conversely, increased-dose levonorgestrel in combination with either 600 or 400 mg of efavirenz was sufficient to restore levonorgestrel concentrations to levels similar to those observed in the 150 mg levonorgestrel control group 48 weeks post-implant-placement (efavirenz:control geometric mean ratio = 0.86 and 1.03, respectively). Conclusions: These results suggest that the clinically significant DDI between efavirenz and levonorgestrel is likely to persist despite efavirenz dose reduction, whereas dose escalation of implantable levonorgestrel may represent a successful clinical strategy to circumvent efavirenz-levonorgestrel DDIs and will be of use to inform clinical trial design to assess coadministration of efavirenz and levonorgestrel implants.
Asunto(s)
Terapia Antirretroviral Altamente Activa/métodos , Benzoxazinas/farmacocinética , Anticonceptivos Femeninos/farmacocinética , Interacciones Farmacológicas , Levonorgestrel/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Adolescente , Adulto , Alquinos , Benzoxazinas/administración & dosificación , Anticonceptivos Femeninos/administración & dosificación , Ciclopropanos , Femenino , Humanos , Levonorgestrel/administración & dosificación , Persona de Mediana Edad , Modelos Estadísticos , Plasma/química , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Adulto JovenRESUMEN
Pharmaceutical excipients are no longer considered inert and have been shown to influence the activity of metabolic enzymes and transporters, resulting in altered pharmacokinetics of substrate drugs. In this study, the effect of 25 excipients commonly used in drug formulations were investigated for their effect on P-glycoprotein (P-gp) activity. The effect of excipients on P-gp were assessed by measuring the change in the cellular accumulation of a P-gp substrate, digoxin, in MDCK-MDR1 (Madin Darby canine kidney transfected with multidrug resistance 1 gene) cells. The cells were exposed to low (10 µM) and high (200 µM) concentrations of excipient along with 10 µM digoxin. Excipient concentrations were chosen to span the range of concentrations previously used for investigating activities in vitro. At 10 µM of excipient, an increase in the intracellular digoxin concentration was seen with d-α-tocopherol poly-(ethylene glycol) succinate (Vit-E-PEG; p = 0.002), poly(ethylene oxide)20 sorbitan monooleate (Tween 80; p = 0.001), cetyltrimethylammonium bromide (CTAB; p = 0.021), poly(ethylene oxide)35 modified castor oil (Cremophor EL; p = 0.01), polyethylene glycol15-hydroxystearate (Solutol HS 15; p = 0.006), and poly(ethylene glycol) hexadecyl ether (Brij 58; p = 0.001). At 200 µM, Vit-E-PEG ( p < 0.0001), sodium 1,4-bis (2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate (AOT; p < 0.0001), Tween 80 ( p < 0.0001), CTAB ( p = 0.004), poly(ethylene oxide)20 sorbitan monolaurate (Tween 20; p < 0.0001), Cremophor EL ( p < 0.0001), Solutol HS 15 ( p < 0.0001), Brij 58 ( p < 0.0001), and sodium carboxymethyl cellulose (NaCMC; p = 0.006) increased intracellular digoxin significantly. Concentration-dependent inhibition of P-gp was then investigated for selected excipients giving an IC50 for Vit-E-PEG (12.48 µM), AOT (192.5 µM), Tween 80 (45.29 µM), CTAB (96.67 µM), Tween 20 (74.15 µM), Cremophor EL (11.92 µM), Solutol HS 15 (179.8 µM), Brij 58 (25.22 µM), and NaCMC (46.69 µM). These data add to the growing body of evidence demonstrating that not all excipients are inert and will aid excipient choice for rational formulation development.
Asunto(s)
Composición de Medicamentos/métodos , Excipientes/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Digoxina/análisis , Digoxina/metabolismo , Perros , Células de Riñón Canino Madin Darby , TransfecciónRESUMEN
Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CLint.app.) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CLint.app. in a concentration-dependent manner. Linear regression analysis showed that log10 RTV and log10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CLint.app., where ß was equal to -234 (95% confidence interval [CI] = -275 to -193; P < 0.0001) and -73 (95% CI = -89 to -57; P < 0.0001), respectively. RTV was more effective in lowering 10 µM RIF-induced elevations in DRV CLint.app. (half-maximal [50%] inhibitory concentration [IC50] = 0.025 µM) than COBI (IC50 = 0.223 µM). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CLint.app., with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis.
Asunto(s)
Antirreumáticos/farmacocinética , Antituberculosos/farmacocinética , Cobicistat/farmacocinética , Darunavir/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Rifampin/farmacocinética , Ritonavir/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Antirreumáticos/uso terapéutico , Antituberculosos/uso terapéutico , Células Cultivadas , Cobicistat/uso terapéutico , Darunavir/uso terapéutico , Interacciones Farmacológicas , Quimioterapia Combinada , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Humanos , Tasa de Depuración Metabólica/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Rifampin/uso terapéutico , Ritonavir/uso terapéutico , Tuberculosis Pulmonar/microbiologíaRESUMEN
Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight-1) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median maximum concentrations of drug (Cmax) were predicted to be 3,184 ng ml-1 (interquartile range [IQR], 2,219 to 4,851 ng ml-1), 49.9 ng ml-1 (IQR, 36.6 to 69.7 ng ml-1), and 50,343 ng ml-1 (IQR, 38,351 to 65,799 ng ml-1) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg-1), the median plasma and brain tissue concentrations in rats were 69.7 ng ml-1 (IQR, 44.9 to 130.6 ng ml-1) and 702.9 ng ml-1 (IQR, 475.5 to 1,018.0 ng ml-1), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Benzoxazinas/farmacocinética , Encéfalo/metabolismo , Modelos Estadísticos , Administración Oral , Alquinos , Animales , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/líquido cefalorraquídeo , Benzoxazinas/sangre , Benzoxazinas/líquido cefalorraquídeo , Simulación por Computador , Ciclopropanos , Esquema de Medicación , Cálculo de Dosificación de Drogas , Humanos , Masculino , Proteínas del Tejido Nervioso/metabolismo , Unión Proteica , Ratas , Ratas Wistar , Distribución TisularRESUMEN
Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (Cmax; 335 ng/ml), time to Cmax (Tmax; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC0-24; 3,045 ng · h/ml), and concentration at 24 h (C24; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated Cmax (238 ng/ml), Tmax (3 h), AUC0-24 (3,036 ng · h/ml), and C24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies.