Pharmacogenetics of antiretroviral drugs used for prevention of mother-to-child transmission of HIV during pregnancy and lactation

The use of antiretroviral therapy (ART) during pregnancy and lactation has significantly reduced the rate of mother-to-child transmission (MTCT) of HIV. However, pregnancy is known to affect the pharmacokinetics of many drugs, including key antiretroviral (ARV) drugs. In addition, ARV use during lactation raises questions about unintended exposure of breastfed infants to maternal drugs through breast milk. For drugs with significant genetic contribution to observed pharmacokinetic variability, we hypothesised that polymorphisms in drug disposition genes may accentuate or attenuate pregnancy-induced changes and/or breastfed infants’ exposure. HIV positive pregnant women and nursing mothers taking efavirenz (EFV)- or nevirapine (NVP)-based ART were recruited from three hospitals in Benue State, Nigeria. A novel strategy involving a preliminary pharmacogenetic association study was used to investigate the magnitude of pregnancy-induced changes in EFV and NVP pharmacokinetics in women stratified by single nucleotide polymorphisms (SNPs) in disposition genes. EFV apparent clearance (CL/F) was higher and AUC0-24, Cmax and Cmin were significantly lower in pregnant compared with postpartum women. When stratified based on the SNP with the highest predictive power, pregnant women with CYP2B6 516GG genotype were especially at risk. In the NVP cohort, exposure was also significantly lower in pregnant compared with postpartum women. When stratified based on composite CYP2B6 516G>T and 983T>C genotypes, Cmin was below target in most patients with combined CYP2B6 516GG and 983TT during pregnancy and postpartum. Cmin was below target in at least 50% of pregnant women with one or two variant alleles, compared with 0% in postpartum women. The intensive pharmacokinetics of EFV and NVP in breast milk and pharmacogenetic predictors were described for the first time. Breast milk pharmacokinetic parameters of EFV in breast milk differed significantly between patient groups stratified by CYP2B6 516G>T. The median time averaged milk-to-plasma concentration (M/P) ratio was 1.10 (range: 0.57-1.71) and the paediatric dose weight-adjusted exposure index was 4.05% (1.08-13.8). The resulting infant plasma concentration was influenced by CYP2B6 516G>T, highest up to 8 days of age at 1590 ng/mL (190-4631) and decreased by about 90% in the age stratum 9 days to 3 months. NVP AUC0-12, Cmax and Cmin in breast milk were significantly lower in patients with composite CYP2B6 516GG/983TT than those with at least one variant allele. The M/P ratio was 0.88 (0.74-1.2) and paediatric dose weight-adjusted exposure index was 3.64% (1.99-9.88). Infant plasma concentration differed significantly based on CYP2B6 516G>T/983T>C and CYP3A4 20230G>A (*1G), highest in those exposed through both breast milk and post-exposure prophylaxis compared with either alone. A breastfeeding physiologically-based pharmacokinetic (PBPK) model to predict infant exposure to maternal drugs through breast milk was developed and validated, with over 90% of all individual observed data points within the predictive interval. This thesis presents details about five different studies where these findings were observed. Their clinical implications in the context of current knowledge and practice were also explored

A Holistic Review of the Preclinical Landscape for Long-Acting Anti-infective Drugs Using HIV as a Paradigm

Abstract 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.</jats:p

Statistical Analysis of Impact of Non-Oil Tax Revenue on the Nigeria Economy

The objective of this paper is to explore the impact of Non-oil tax revenue on the economic growth of Nigeria as proxies by the real gross domestic product (RGDP).  The ordinary least square (OLS) regression analysis was adopted to explore the relationship between the RGDP (the dependent variable) and (the independent variables),  company income tax, (CIT), Custom and Excise Duty, CED, Value added Tax,(VAT), Federal government independent revenue, (FGIR),  and Education taxes (ET), heads over the period 1995-2015. Augmented Dickey Fuller unit root test was employed to examine the stationary properties of the series, Johansen co-integration test was applied to determine the long-run relationship among study variables while fully modified ordinary least squares co-integrating regression equation was estimated to determine the impacts of Non –oil tax revenue on RGDP. Granger causality test base on Toda and yamamoto procedure was then applied to determine the direction on causality. The ADF unit root tests indicate that all the variable is integrated of order one, 1(1). The Johansen co-integration test reveals that the variable under are co-integrated and do not wander away from each other  A simple hypothesis was formulated in the null form which states that there is no significant relationship between federally collected Non-oil tax revenue and the RGDP in Nigeria.  The regression result indicated a very positive and significant relationship.  However some of the indicator did not have much significant RGDP as they fell below the level expected.  The anomaly was attributed to dysfunctional ties in the income tax system, loopholes in tax laws and inefficient tax administration.  Suggestions were made as to strategies to be adopted to improve the system of tax administration and tax policy in other to increase Non-oil tax revenue generation. DOI: 10.7176/JESD/10-6-08 Publication date:March 31st 201

Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz

PURPOSE: To treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design. METHODS: In vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600 mg once daily) was administered to 50 virtual subjects for 14 days. This was followed by concomitant administration of artemether (80 mg eight hourly) for the first two doses and 80 mg (twice daily) for another two days. RESULTS: Simulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether C(max) by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240 mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether. CONCLUSIONS: The model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition

Development, validation and clinical application of a method for the simultaneous quantification of lamivudine, emtricitabine and tenofovir in dried blood and dried breast milk spots using LC-MS/MS

Objectives To present the validation and clinical application of a LC–MS/MS method for the quantification of lamivudine (3TC), emtricitabine (FTC) and tenofovir (TFV) in dried blood spots (DBS) and dried breast milk spots (DBMS). Methods DBS and DBMS were prepared from 50 and 30 μL of drug-spiked whole blood and human breast milk, respectively. Following extraction with acetonitrile and water, chromatographic separation utilised a Synergi polar column with a gradient mobile phase program consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Detection and quantification was performed using a TSQ Quantum Ultra triple quadrupole mass spectrometer. The analytical method was used to evaluate NRTI drug levels in HIV-positive nursing mothers-infant pairs. Results The assay was validated over the concentration range of 16.6–5000 ng/mL for 3TC, FTC and TFV in DBS and DBMS except for TFV in DBMS where linearity was established from 4.2–1250 ng/mL. Intra and inter-day precision (%CV) ranged from 3.5–8.7 and accuracy was within 15% for all analytes in both matrices. The mean recovery in DBS was >61% and in DBMS >43% for all three analytes. Matrix effect was insignificant. Median AUC0-8 values in maternal DBS and DBMS, respectively, were 4683 (4165–6057) and 6050 (5217–6417) ng h/mL for 3TC, 3312 (2259–4312) and 4853 (4124–6691) ng h/mL for FTC and 1559 (930–1915) and 56 (45–80) ng h/mL for TFV. 3TC and FTC were quantifiable (>16.6 ng/mL) in DBS from 2/6 and 1/6 infants respectively whereas TFV was undetectable in all infants. Conclusions DBS and DBMS sampling for bioanalysis of 3TC, FTC and TFV is straightforward, robust, accurate and precise, and ideal for use in low-resource settings

Physiologically-based pharmacokinetic modelling of infant exposure to efavirenz through breastfeeding

Background: Very little is known about the level of infant exposure to many drugs commonly used during breastfeeding. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for predicting infant exposure to maternal efavirenz through breastmilk. Methods: A breastfeeding PBPK model combining whole-body maternal and infant sub-models was constructed from drug-specific and system parameters affecting drug disposition using mathematical descriptions. The model was validated against published data on the pharmacokinetics of efavirenz in nursing mother-infant pairs. Further simulations were conducted to assess exposure in the context of the 400 mg reduced dose of efavirenz as well as best- and worse-case scenarios. Results: The model adequately described efavirenz pharmacokinetics, with over 80% of observed data points (203 matched breast milk and plasma pairs) within the predictive interval. All parameters were within 2-fold difference of clinical data. Median (range) predicted versus observed breast milk AUC 0-24 , C max and C min at the standard 600 mg dose were 75.0 (18.5-324) versus 68.5 (26.3-257) µg.hr/mL, 4.56 (1.17-16.0) versus 5.39 (1.43-18.4) µg/mL, and 2.11 (0.38-12.3) versus 1.68 (0.316-9.57) µg/mL, respectively. Predicted plasma AUC 0-24 , C max and C min at 400 mg reduced dose were similar to clinical data from non-breastfeeding adults. Model-predicted infant plasma concentrations were similar to clinical data, 0.15 (0.026–0.78) μg/mL at the 400 mg maternal dose in pooled analysis, approximately 25% lower than simulated exposure at 600 mg. The maximum exposure index was observed in the youngest infants, 5.9% (2.2-20) at 400 mg and 8.7% (3.2-29) at 600 mg. Thirteen and 36% of 10 days-1 month old infants were predicted to have exposure index above the 10% recommended threshold at 400 mg and 600 mg maternal dose, respectively. Conclusions: This application of PBPK modelling opens up opportunities for expanding our understanding of infant exposure to maternal drugs through breastfeeding

Comparison of efavirenz levels in blood and hair with pharmacy refills as measures of adherence and predictors of viral suppression among people living with HIV in Nigeria

BackgroundStrategies 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.MethodsPaired 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.ResultsBased 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.ConclusionsEFV 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

The global, regional, and national burden of adult lip, oral, and pharyngeal cancer in 204 countries and territories:A systematic analysis for the Global Burden of Disease Study 2019

Importance Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.Objective To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence Review The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.Findings In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and Relevance In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts