hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole.

Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 µM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 µM; hERG IC50 = 0.63 µM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 µM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 µM, and liver-stage PbHepG2 IC50 = 2.30 µM), good microsomal metabolic stability (MLM CLint < 11 µL·min-1·mg-1, EH < 0.33), and solubility (150 µM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (log D7.4 = -0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.

Population Pharmacokinetic Modeling and Dose Optimization of Acetaminophen and its Metabolites Following Intravenous Infusion in Critically ill Adults.

BACKGROUND AND OBJECTIVE: Acetaminophen (paracetamol) is a ubiquitously administered drug in critically ill patients. Considering the dearth of literature, we evaluated the population pharmacokinetics of intravenous acetaminophen and its principal metabolites (sulfate and glucuronide) in this population. METHODS: Critically ill adults receiving intravenous acetaminophen were included in the study. One to three blood samples were withdrawn per patient for the estimation of acetaminophen, and its metabolites (acetaminophen glucuronide and acetaminophen sulfate). High-performance liquid chromatography was used for measuring serum concentrations. We used nonlinear mixed-effect modeling for estimating the primary pharmacokinetic parameters of acetaminophen and its metabolites. The effect of covariates was evaluated followed by dose optimization using Monte Carlo simulation. Patient factors such as demographic information, liver and renal function tests were used as covariates in population pharmacokinetic analysis. The therapeutic range for serum acetaminophen concentration was considered to be 66-132 µM, while 990 µM was considered as the threshold for toxic concentration. RESULTS: Eighty-seven participants were recruited. A joint two-compartment acetaminophen pharmacokinetic model linked to glucuronide and sulfate metabolite compartments was used. The central and peripheral volume distributions were 7.87 and 8.87 L/70 kg, respectively. Estimated clearance (CL) was 0.58 L/h/70 kg, while intercompartmental clearance was 44.2 L/h/70 kg. The glucuronide and sulfate metabolite CL were 22 and 94.7 L/h/70 kg, respectively. Monte Carlo simulation showed that twice-daily administration of acetaminophen would result in a relatively higher proportion of patient population achieving and retaining serum concentrations in the therapeutic range, with reduced risk of concentrations remaining in the toxic range. CONCLUSION: A joint pharmacokinetic model for intravenous acetaminophen and its principal metabolites in a critically ill patient population has been developed. Acetaminophen CL in this patient population is reduced. We propose a reduction in the frequency of administration to reduce the risk of supra-therapeutic concentrations in this population.

Integrating Pharmacokinetic-Pharmacodynamic Modeling and Physiologically Based Pharmacokinetic Modeling to Optimize Human Dose Predictions for Plasmodium falciparum Malaria: a Chloroquine Case Study.

The translation of a preclinical antimalarial drug development candidate to the clinical phases should be supported by rational human dose selection. A model-informed strategy based on preclinical data, which incorporates pharmacokinetic-pharmacodynamic (PK-PD) properties with physiologically based pharmacokinetic (PBPK) modeling, is proposed to optimally predict an efficacious human dose and dosage regimen for the treatment of Plasmodium falciparum malaria. The viability of this approach was explored using chloroquine, which has an extensive clinical history for malaria treatment. First, the PK-PD parameters and the PK-PD driver of efficacy for chloroquine were determined through a dose fractionation study in the P. falciparum-infected humanized mouse model. A PBPK model for chloroquine was then developed for predicting the drug's PK profiles in a human population, from which the human PK parameters were determined. Lastly, the PK-PD parameters estimated in the P. falciparum-infected mouse model and the human PK parameters derived from the PBPK model were integrated to simulate the human dose-response relationships against P. falciparum, which subsequently allowed the determination of an optimized treatment. The predicted efficacious human dose and dosage regimen for chloroquine were comparable to those recommended clinically for the treatment of uncomplicated, drug-sensitive malaria, which provided supportive evidence for the proposed model-based approach to antimalarial human dose predictions.

Parental reporting of adverse drug reactions in South Africa: An online survey.

BACKGROUND: The high incidence of adverse drug reactions (ADRs) in children is of global concern. Enhancing the reporting of ADRs could contribute to making safer medicines available to children. AIM: To assess parents' awareness of reporting ADRs and their knowledge on the reporting procedures in South Africa. SETTING: South African parents with online access. METHOD: A quantitative descriptive study was conducted based on an anonymous voluntarily web-based self-administered questionnaire that was distributed through Facebook® and LinkedIn™ to parents in South Africa. RESULTS: The questionnaire was completed voluntarily by 206 respondents. The majority of participants (70.9%) were aware of the term ADR. Significant associations between not being aware of the term ADR and single marital status, lower education level, not having private medical aid and accessing public clinics for medical services were found. The majority (66.5%) of participants did report an ADR to a healthcare professional whilst only 15% reported it to a product manufacturer. More than half of the participants (58.7%) knew how to report ADRs whilst 72.8% knew what type of ADRs to report. Almost a third (32.5%) did not know where more information on ADR reporting could be found or how ADRs could be reported (31.5%). CONCLUSION: The majority of the respondents were aware of the term ADR, indicative of a good knowledge basis on which ADRs to report and the importance of reporting ADRs. However, gaps in the respondents' knowledge were identified which highlighted specific groups of individuals to be targeted to increase ADR awareness and improve the knowledge on the reporting process.

Population pharmacokinetic-pharmacodynamic modeling of acetaminophen in preterm neonates with hemodynamically significant patent ductus arteriosus.

BACKGROUND: Pharmacokinetics (PK) of intravenous acetaminophen has not been assessed in preterm neonates with hemodynamically significant patent ductus arteriosus (PDA). Moreover, there is a lack of data evaluating the association between PK and pharmacodynamics (PD) of acetaminophen in hemodynamically significant PDA. Hence, we performed a population PK-PD modeling of acetaminophen in preterm neonates with hemodynamically significant PDA. METHODS: A prospective, observational study was carried out in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen (15 mg/kg six hourly) for maximum of nine days. The diameter of the ductus arteriosus was measured using General Electric Vivid 7® (echocardiography) and was the PD measure. The PK-PD modeling was performed using Monolix 2019R2. We performed Monte Carlo (MC) simulations to determine the probability of ductus arteriosus closure from first to the ninth day of acetaminophen treatment. RESULTS: Fifty-five neonates were recruited. A one-compartment model with first-order elimination described well the PK of acetaminophen. Clearance (CL) and volume of distribution (Vd) for typical neonate weighing 0.98 kg was 0.0452 L/h and 1.18 L, respectively. A combination of an Imax model with effect compartment and an exponential disease progression model described well the PD of acetaminophen. The average baseline diameter of the ductus arteriosus (E0) was 2.53 mm while IC50 was 0.477 µg/mL. The disease progression rate constant (Kprog) and effect compartment transfer rate constant (ke0) were 0.00425 h-1 and 0.000103 h-1, respectively. MC simulations of the current dosing regimen revealed a probability of 73.7% ductus arteriosus closure compared to 83.8% with 20 mg/kg six hourly dose. CONCLUSION: The PK-PD model developed can be used for dosing acetaminophen in premature neonates with hemodynamically significant PDA. Intravenous dose of 20 mg/kg intravenously every six hours is likely to provide a better therapeutic effect than the existing dosing regimen.

Population Pharmacokinetics and Dose Optimization of Vancomycin in Critically Ill Children.

BACKGROUND AND OBJECTIVE: Critically ill children may exhibit varied vancomycin pharmacokinetic parameters mainly due to altered protein binding, extracellular volume, and renal elimination. The objective of this study was to assess the pharmacokinetics of vancomycin in critically ill children and determine the optimum dose regimen. METHODS: This was a cross-sectional study of critically ill children admitted to a pediatric intensive care unit. They received vancomycin dose of 15 mg/kg every 8 h for mild infections or every 6 h if infection was moderate or severe. A nonlinear mixed-effects modeling approach was applied in estimating pharmacokinetic parameters using Monolix 2019R2®. We performed Monte Carlo simulations to assess and optimize the dosing regimen using Simulx®. We used the ratio of the area under the concentration-time curve up to 24 h to minimum inhibitory concentration (AUC0-24/MIC) ≥ 400 as the pharmacokinetic-pharmacodynamic target. RESULTS: Fifty-eight critically ill children with 145 concentrations were included in the present study. A one-compartment pharmacokinetic model with linear elimination described the concentration-time profile well. The estimated median (95% confidence intervals) volume of distribution (Vd) was 13.3 (10.8-16.5) l and clearance (CL) was 1.23 (1.03-1.45) l/h. Creatinine clearance significantly affected the CL of vancomycin. Monte Carlo simulations revealed that a dose of either 15 mg/kg 6 hourly or 20 mg/kg 8 hourly was likely to result into most critically ill children attaining the vancomycin lead pharmacokinetic-pharmacodynamic target. CONCLUSION: We established pharmacokinetic parameters of vancomycin for critically ill children. We also observed that the current dosing regimen practiced in the intensive care unit was inadequate for achieving the pharmacokinetic-pharmacodynamic target. We recommend vancomycin dose escalation in critically ill pediatric patients from 15 mg/kg 8 hourly (current dosing regimen) to either 6 hourly or 20 mg/kg 8 hourly with intense therapeutic drug monitoring for adverse effects.

Access to chronic medicines: patients' preferences for a last kilometre medicine delivery service in Cape Town, South Africa.

BACKGROUND: Chronic patients are required to access their chronic medicines on a regular basis, often only to refill their repeat prescriptions. Adherence to chronic medicines is challenging and has stimulated health care providers to devise differentiated service delivery models of care to decentralise chronic medicine distribution to decrease the frequency of medicine collection at health care facilities. One such option includes a last kilometre medicine delivery service. This study investigated chronic patients' preferences for a last kilometre medicine delivery service model. METHODS: An exploratory non-randomised quantitative study was conducted over 4 weeks at four public sector primary health care facilities in Cape Town, South Africa. Data was collected on a structured questionnaire from chronic patients queuing to receive medication at each facility's pharmacy waiting area. Patient demographics were noted to align with preferences for chronic medicine service delivery characteristics including; mobile ordering, fee for service and location for delivery. Chi-square test and frequencies were employed to analyse data using SPSS version 23. RESULTS: A total of 116 patients participated in this study. Most were interested in a medicine delivery service (80.2%) and were willing to use a mobile application to order their medicines (84.5%). Almost all patients (96.8%) preferred that their medicines be delivered to their home. More than three quarters of participants were willing to pay for the service (77.6%). Chi-square test showed that gender, age group, employment status, distance to the health facility and /or average waiting time at the clinic significantly influenced the preference for certain characteristics of the medicine delivery service (p < 0.05). CONCLUSION: Most participants were interested in a last kilometre medicine delivery service, especially those older than 45 years, waiting for more than 6 h at the facility, and staying within one kilometre radius of the clinic. More studies are needed to establish the influence of patients' employment status and the distance to health facility on interest in the medicine delivery service.

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug-resistant tuberculosis.

INTRODUCTION: Ethionamide is part of the drug-resistant tuberculosis regimen whose pharmacokinetic (PK) and pharmacodynamic (PD) information is limited. The aim of the study was to describe the PK and simulate doses to assess PD attainment. METHODS: This was an observational population PK study of patients admitted for drug-resistant tuberculosis at a hospital in South Africa. Nonlinear mixed-effects modelling implemented in Monolix 2019R2 was used to estimate population pharmacokinetic parameters. We performed Monte Carlo simulations to assess and optimise the dose regimen. The target Cmax range was 2.5-5 µg/mL, which is within the minimum inhibitory concentration (MIC) range. The target AUC0-24h was 140.5 µg*h/mL, which corresponds to the PK/PD target ratio AUC0-24h /MIC of 56.2. RESULTS: A one-compartment pharmacokinetic model with a lag-time, first-order absorption and elimination best described the PK of ethionamide. The lag-time, absorption rate constant (ka), volume of distribution (V/F) and clearance (Cl/F) were 0.66 hours, 0.434 h-1 , 180 L and 99.5 L/h, respectively, for a typical individual weighing 52.6 kg. Between-subject variability in lag-time, ka, V/F and Cl/F were 38%, 92%, 168% and 120%, respectively. Simulation of the recommended doses of 15-20 mg/kg, 500 mg, 750 mg and 1000 mg for patients in the weight bands <33, 33-50, 51-70 and >70 kg resulted in <17% and 3% of the patients achieving the target Cmax and AUC0-24h , respectively. CONCLUSION: There is high variability in ethionamide PK and very few patients attain the desired target exposure at standard or optimised doses. We propose individualised dose regimen optimisation.

Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates.

BACKGROUND: The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), varies between paediatric and adult patients. OBJECTIVE: The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen. METHODS: This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units. They all received vancomycin 15 mg/kg every 12 h. Blood was sampled just before administration of the third, sixth and ninth vancomycin dose. Pharmacokinetic parameters were estimated using a Bayesian approach implemented in Monolix 2018R2 software. Covariates assessed included postmenstrual age, current weight, creatinine clearance, albumin, gestational age, body surface area and current age. We used Monte Carlo simulations for dose regimen optimisation targeting area under the concentration-time curve up to 24 h (AUC0-24h) of ≥ 400 mg × h/L. RESULTS: In total, 19 preterm neonates were enrolled in the study with a median age of 14 (3-58) days. A one-compartment model with linear elimination best described the pharmacokinetics of vancomycin. Volume of distribution and clearance was 0.88 L and 0.1 L/h, respectively, for a typical neonate weighing 1.48 kg. Simulation of the current dose regimen showed that 27.5% of the neonates would achieve the target AUC0-24h of ≥ 400 mg × h/L, and 70.7% of the neonates would achieve it with 12 mg/kg every 8 h. CONCLUSION: The majority of the neonates were under dosed. Vancomycin 12 mg/kg should be administered every 8 h over 1 h infusion to improve the likelihood of achieving the AUC0-24h target of ≥ 400 mg × h/L. This target is considered optimal for MRSA infections, where the vancomycin minimum inhibitory concentration is ≤ 1 µg/mL.

Amount of Cycloserine Emanating from Terizidone Metabolism and Relationship with Hepatic Function in Patients with Drug-Resistant Tuberculosis.

BACKGROUND AND OBJECTIVES: The dosing of cycloserine and terizidone is the same, as both drugs are considered equivalent or used interchangeably. Nevertheless, it is not certain from the literature that these drugs are interchangeable. Therefore, the amount of cycloserine resulting from the metabolism of terizidone and the relationship with hepatic function were determined. METHODS: This prospective clinical study involved 39 patients with drug-resistant tuberculosis admitted for an intensive phase of treatment. Cycloserine pharmacokinetic parameters for individual patients, like area under the curve (AUC), clearance (CLm/F), peak concentration (Cmax) and trough concentration (Cmin), were calculated from a previously validated joint population pharmacokinetic model of terizidone and cycloserine. Correlation and regression analyses were performed for pharmacokinetic parameters and unconjugated bilirubin (UB), conjugated bilirubin (CB), albumin, the ratio of aspartate transaminase to alanine aminotransferase (AST/ALT), or binding affinity of UB to albumin (Kaf), using R statistical software version 3.5.3. RESULTS: Thirty-eight patients took a daily dose of 750 mg terizidone, while one took 500 mg. The amount of cycloserine [median (range)] that emanated from terizidone metabolism was 51.6 (0.64-374) mg. Cmax (R2 = 22%, p = 0.003) and Cmin (R2 = 10.6%, p = 0.044) were significantly associated with increased CB concentration. Cmax was significantly associated with increased Kaf (R2 = 10.1%, p = 0.048), while high CLm/F was significantly associated with decreased AST/ALT (R2 = 21%, p = 0.003). CONCLUSIONS: Cycloserine is not interchangeable with terizidone, as amounts are lower than expected. Cycloserine may be a predisposing factor to the development of hyperbilirubinaemia, as CLm/F is affected by hepatic function.

Steady-state population pharmacokinetics of terizidone and its metabolite cycloserine in patients with drug-resistant tuberculosis.

AIMS: Despite terizidone being part of the second-line recommended drugs for treatment of drug-resistant tuberculosis (DR-TB), information on its pharmacokinetics is scarce. The aim of this study was to describe the steady-state population pharmacokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients with DR-TB and determine the effect of patient characteristics. METHODS: This clinical study involved 39 adult DR-TB patients admitted to Brewelskloof Hospital in Cape Town, South Africa for intensive treatment phase. Blood samples were collected at predose and 0.5, 1, 2, 3, 3.5, 4, 8, 16 and 24 hours after drug administration. The estimation of PPK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R1. Free-fat mass was used to perform allometric scaling on disposition parameters. RESULTS: A 1-compartment model best described the pharmacokinetics of terizidone and cycloserine. A modified transit compartment model described the absorption of terizidone. The parameters of terizidone model were mean transit time (1.7 h), absorption rate constant (2.97 h-1 ), apparent volume of distribution (Vp/F: 13.4 L) and apparent total clearance (0.51 L h-1 ). In the joint model, apparent fraction of terizidone converted to cycloserine was 0.29 while apparent clearance of terizidone via other routes and apparent cycloserine clearance was 0.1 L h-1 and 2.94 L h-1 , respectively. Serum albumin had significant effect on Vp/F. CONCLUSIONS: The developed PPK model described well the concentration-time profile for terizidone and cycloserine in DR-TB patients. High albumin concentration was associated with low Vp/F.

Sensitive Ultra-performance Liquid Chromatography Tandem Mass Spectrometry Method for Determination of Cycloserine in Plasma for a Pharmacokinetics Study.

A simple and sensitive ultra-performance liquid chromatography tandem mass spectrometry method has been developed and validated for the analysis of cycloserine in patients' plasma. Using methanol, cyloserine and propranolol (internal standard (IS)) was extracted from plasma by protein precipitation procedure. The chromatographic separation was successfully achieved on Phenomenex KinetexTM PFP C18 (2.1 mm × 100 mm, 2.6 µm) reversed-phase column. Acidified with 0.1% formic acid, water and acetonitrile were used as mobile phases for gradient elution. Cycloserine and IS were detected by Xevo® TQ MS triple quadrupole tandem mass spectrometer. The transition of protonated precursor to product ion were monitored at 103 → 75 m/z and 260.2 → 183 m/z for cycloserine and IS, respectively. The lower limit of quantification was 0.01 µg/mL. The method was linear over the concentration range 0.01-50 µg/mL with average coefficient of determination of 0.9994. The within-run and between-run precision and accuracy were in the range 3.7-19.3% (RSD) and 98.7-117.3%, respectively. Processed cycloserine sample was stable for 48 hours at 8°C and after three freeze-thaw cycles. The extraction efficiency ranged between 88.7 and 91.2%. The method was successfully applied in a pharmacokinetic study for the determination of cycloserine in plasma of patients with drug-resistant tuberculosis.

Population Pharmacokinetic Modelling of Pyrazinamide and Pyrazinoic Acid in Patients with Multi-Drug Resistant Tuberculosis.

BACKGROUND AND OBJECTIVES: Pyrazinamide, a drug used in the regimen for the treatment of drug-sensitive tuberculosis, is also used for the treatment of multidrug-resistant tuberculosis (MDR-TB). We aimed to describe the population pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, in patients with MDR-TB and characterise the effects of demographic variables. METHODS: This was a non-randomised clinical study involving 51 adult patients admitted for the intensive phase of MDR-TB treatment. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8, 16 and 24 h after drug administration. Plasma concentrations of pyrazinamide and pyrazinoic acid were analysed using a validated LC-MS/MS method. Nonlinear mixed-effects modelling using Monolix 2018R1 software was employed to estimate population pharmacokinetic parameters. RESULTS: A one-compartment pharmacokinetic model with transit compartment absorption process and first-order elimination best described the pyrazinamide and pyrazinoic acid concentration-time data. The estimated population pharmacokinetic parameters were 0.7 h, 3.38 h-1, 57.1 l, 4.37 L/h and 10.5 L/h for mean transit time, absorption rate constant, apparent distribution volume for pyrazinamide, and apparent clearance for pyrazinamide and pyrazinoic acid (CLm/F), respectively. These parameters were not affected by patient age, HIV status or sex. The parameter variability in CLm/F was the highest (83.5%), while the rest of the parameters ranged from 16.2 to 58%. CONCLUSIONS: The developed population pharmacokinetic model adequately described the disposition of pyrazinamide and pyrazinoic acid and can be useful for dose determination of pyrazinamide in patients with MDR-TB.

Analysis of terizidone in plasma using HPLC-UV method and its application in a pharmacokinetic study of patients with drug-resistant tuberculosis.

A chromatographic method has been developed and validated for the first time for analysis of terizidone in plasma. Terizidone was extracted from plasma by protein precipitation using a mixture of acetonitrile and methanol (1:1, v/v). The chromatographic separation was achieved with a gradient of acetonitrile and water both containing 0.1% formic acid on a Supelco Discovery® HS C18 (150 × 4.6 mm, 5 µm) reversed-phase column. Propranolol was used as the internal standard. The total run-time was 18 min. The calibration standard concentrations ranged between 3.125 and 200 µg/mL and calibration curves were linear with coefficient of determination values in the range of 0.9988-0.9999. The inter- and intra-day assay precision (percentage relative standard error) was <15% while mean accuracy was 107%. The mean extraction efficiencies of terizidone and IS were 76 and 89%, respectively. The validation results demonstrated that the method was selective and sensitive, and that terizidone was stable under the studied conditions. The method was successfully applied in a population pharmacokinetic study. The mean plasma concentration of terizidone in patients at all sampling time points was 51.8 ± 28 µg/mL. The method was simple, cheap and hence suitable for therapeutic drug monitoring of terizidone.

Associations between plasma tenofovir concentration and renal function markers in HIV-infected women.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been associated with kidney tubular dysfunction and reduced renal function. Limited studies were performed in Europe and Asia that related plasma tenofovir (TFV) concentration with renal function; no such studies to date have been performed on Africans. OBJECTIVE: To investigate the correlation between plasma tenofovir (TFV) concentration and certain renal function markers in HIV-infected women on TDF antiretroviral therapy (ART). These markers were also compared to a HIV-uninfected control group. METHODS: HIV-infected women (n = 30) on TDF-based ART were matched with 30 controls for age and body mass index. Renal markers analysed were estimated glomerular filtration rate (eGFR), creatinine clearance (CrCl), serum creatinine, albuminuria, glucosuria, serum urea, serum uric acid, urine sodium and maximum tubular reabsorption of phosphate. Baseline eGFR and CrCl data were obtained retrospectively for the HIV-infected women. Plasma TFV was assayed using a validated HPLC-MS/MS method. Stepwise regression, Mann-Whitney test, unpaired and paired t-tests were applied in the statistical analyses. RESULTS: TFV concentration was independently associated with albuminuria (adjusted r2 = 0.339; p = 0.001) in HIV-infected women. In the adjusted (weight) analysis, eGFR (p = 0.038), CrCl (p = 0.032) and albuminuria (p = 0.048) were significantly higher in HIV-infected compared to the uninfected women, but eGFR was abnormally high in HIV-infected women. Both eGFR (p < 0.001) and CrCl (p = 0.008) increased from baseline to follow-up in HIV-infected women. CONCLUSION: Plasma TFV concentration was associated with increased albuminuria in HIV-infected women in this sub-study. Both eGFR and CrCl were increased in HIV-infected women from baseline. These findings should be confirmed in larger studies, and hyperfiltration in HIV-infected women warrants further investigation.