Pharmacokinetics of Generic Pediatric Dolutegravir Dispersible Tablet in Thai Young Children Living With HIV Weighing Below Twenty Kilograms.

INTRODUCTION: Dolutegravir (DTG) dispersible tablet (DTG-DT) is a pediatric-friendly formulation. We aimed to describe the pharmacokinetics and virologic responses of generic DTG-DT in children weighing <20 kg. METHODS: Children living with HIV-1 and <7 years of age weighing 6 to <20 kg were eligible. A generic 10-mg scored DTG-DT was administered to children using 3 weight bands (WB): WB1 (6 to <10 kg), WB2 (10 to <14 kg) and WB3 (14 to <20 kg), at doses of 20 mg (higher than World Health Organization recommendation of 15 mg), 20 mg and 25 mg, respectively. Steady-state intensive pharmacokinetics (PK) was performed in fasting condition with blood sampling at predose and 1, 2, 3, 4, 6 and 24 hours postdose. DTG PK parameters were estimated using a noncompartmental analysis, and DTG trough concentrations (C 24 ) and 24-hour area under the concentration-time curve were calculated. Comparisons were made with ODYSSEY and IMPAACT 2019. And 90% effective concentration of 0.32 mg/L was used as a reference individual DTG C 24 concentration. RESULTS: From August 2021 to March 2023, 29 Thai children with a median (interquartile range) age of 3.2 (1.5-4.8) years were enrolled; 8 in WB1, 9 in WB2 and 12 in WB3. All children were treatment experienced and 59% had HIV RNA <200 copies/mL. Overall geometric mean (coefficient of variation percentage) DTG C 24 was 1.0 (46%) mg/L [WB1, 0.9 (53%); WB2, 0.9 (27%); WB3, 1.2 (51%)]. Geometric mean (coefficient of variation percentage) 24-hour area under the concentration-time curve was 83.2 (24%) mg h/L [WB1, 84.3 (31%); WB2, 76.9 (16%); WB3, 87.6 (25%)]. At weeks 24 and 48, 90% and 92% of participants had plasma HIV RNA <200 copies/mL. CONCLUSIONS: Generic DTG-DT provided adequate drug exposure in children weighing 6 to <20 kg. The exploratory dose of DTG 20 mg for children weighing 6 to <10 kg showed similar PK parameters to World Health Organization doses in the other WB.

Pharmacokinetics of Generic Pediatric Dolutegravir Dispersible Tablet in Thai Young Children Living With HIV Weighing Below Twenty Kilograms.

INTRODUCTION: Dolutegravir (DTG) dispersible tablet (DTG-DT) is a pediatric-friendly formulation. We aimed to describe the pharmacokinetics and virologic responses of generic DTG-DT in children weighing <20 kg. METHODS: Children living with HIV-1 and <7 years of age weighing 6 to <20 kg were eligible. A generic 10-mg scored DTG-DT was administered to children using 3 weight bands (WB): WB1 (6 to <10 kg), WB2 (10 to <14 kg) and WB3 (14 to <20 kg), at doses of 20 mg (higher than World Health Organization recommendation of 15 mg), 20 mg and 25 mg, respectively. Steady-state intensive pharmacokinetics (PK) was performed in fasting condition with blood sampling at predose and 1, 2, 3, 4, 6 and 24 hours postdose. DTG PK parameters were estimated using a noncompartmental analysis, and DTG trough concentrations (C24) and 24-hour area under the concentration-time curve were calculated. Comparisons were made with ODYSSEY and IMPAACT 2019. And 90% effective concentration of 0.32 mg/L was used as a reference individual DTG C24 concentration. RESULTS: From August 2021 to March 2023, 29 Thai children with a median (interquartile range) age of 3.2 (1.5-4.8) years were enrolled; 8 in WB1, 9 in WB2 and 12 in WB3. All children were treatment experienced and 59% had HIV RNA <200 copies/mL. Overall geometric mean (coefficient of variation percentage) DTG C24 was 1.0 (46%) mg/L [WB1, 0.9 (53%); WB2, 0.9 (27%); WB3, 1.2 (51%)]. Geometric mean (coefficient of variation percentage) 24-hour area under the concentration-time curve was 83.2 (24%) mg h/L [WB1, 84.3 (31%); WB2, 76.9 (16%); WB3, 87.6 (25%)]. At weeks 24 and 48, 90% and 92% of participants had plasma HIV RNA <200 copies/mL. CONCLUSIONS: Generic DTG-DT provided adequate drug exposure in children weighing 6 to <20 kg. The exploratory dose of DTG 20 mg for children weighing 6 to <10 kg showed similar PK parameters to World Health Organization doses in the other WB.

Plasma pharmacokinetics and urinary excretion of tenofovir following cessation in adults with controlled levels of adherence to tenofovir disoproxil fumarate.

OBJECTIVES: The aim was to fully characterize the plasma and urine washout pharmacokinetics of tenofovir (TFV) in adults following 6 weeks of controlled levels of tenofovir disoproxil fumarate (TDF) adherence, in order to inform the utility of clinic-based adherence testing. DESIGN: This was a three-arm, randomized, open-label study in adult volunteers. Participants were randomized to receive TDF 300 mg/emtricitabine (FTC) 200 mg as (1) 7 doses/week (perfect adherence), (2) 4 doses/week (moderate adherence), or (3) 2 doses/week (low adherence). Plasma and urine samples were collected regularly during the 6-week dosing phase and for 4 weeks following drug cessation. RESULTS: Twenty-eight adults were included in this analysis. Median (range) age was 33 (20-49) years. No differences in TFV pharmacokinetic parameters during the washout were observed across the study arms. Small differences in TFV plasma concentrations occurred across arms between 4 and 10 h post-dose. The cumulative amount of TFV excreted in urine was not different at 24 h post-dose, but at 148 h it was 24.8 mg, 21.0 mg, and 17.2 mg for the perfect, moderate, and low adherence arms, respectively (p = 0.043). CONCLUSIONS: Among adults with different TDF adherence patterns, relative differences in plasma concentrations and cumulative urine extraction of TFV were minor following cessation. TFV measurement in plasma or urine is more indicative of last drug ingestion, rather than prior dose patterns.

Semi-quantification of HIV-1 protease inhibitor concentrations in clinical samples of HIV-infected patients using a gold nanoparticle-based immunochromatographic assay.

Individual drug concentration data can be a valuable tool for the clinical management of antiretroviral therapy (ART) for the treatment of HIV infection. High performance liquid chromatography (HPLC) based assays are currently the gold standard for drug measurement but its high cost and requirement of technical expertise limits its widespread use. Simpler user-friendly and inexpensive detection assays are needed. A novel immunochromatographic (IC) strip test to detect HIV-1 protease inhibitors (PIs) was fabricated by combining the proteolysis activity of HIV-protease (PR) and an immunochromatographic reaction. The PIs-IC strip cut-off to detect lopinavir (LPV) concentrations was set at 1,000 ng mL-1. We evaluated this novel PIs-IC strip for the semi-quantification of HIV PIs in plasma samples collected from healthy subjects and HIV-infected patients receiving antiretroviral treatment with and without LPV. LPV plasma drug levels were quantified by HPLC and evaluated (blinded to the HPLC results) using the PIs-IC strip. Results of plasma samples tested using the PIs-IC strip were available within 5 min. Using the PIs-IC strip test the accuracy, specificity and sensitivity were 97.8%, 97.1%, and 100%, respectively, compare to the gold-standard assay, to detect LPV in human plasma samples. This novel PIs-IC strip test could be used as a simple tool for the rapid monitoring of PIs levels in HIV-infected patients, although further clinical evaluation is needed.

Nevirapine Concentrations During the First Month of Life and Maternal Efavirenz Washout in High-Risk HIV-Exposed Infants Receiving Triple Antiretroviral Prophylaxis.

BACKGROUND: Triple-drug infant antiretroviral prophylaxis containing nevirapine (NVP) is increasingly used to prevent HIV transmission among neonates at high risk of HIV infection. Our aim was to describe NVP concentration from birth through the first month of life. METHODS: High-risk HIV-exposed neonates were enrolled in a prospective cohort in Thailand. High-risk neonates defined as maternal HIV RNA >50 copies/mL before delivery or mother received antiretroviral treatment for <12 weeks before delivery. Neonates received zidovudine (4 mg/kg) and lamivudine (2 mg/kg) twice daily, plus NVP (4 mg/kg) once daily (no lead-in) from birth to 6 weeks of life. Infant plasma samples were collected at 1, 2, 14 or 2, 7, 28 days of life. NVP trough concentrations (C24) were estimated using a population pharmacokinetic model and target C24 was ≥0.1 mg/L. "Washout" efavirenz (EFV) concentrations were assessed in infants whose mother received EFV-based antiretroviral treatment. RESULTS: A total of 48 infants were included: 25 (52%) were male and 12 (25%) were preterm (gestational age 34-37 weeks). Median (interquartile range) predicted NVP C24 were 1.34 mg/L (1.13-1.84), 2.24 (2.00-2.59), 2.78 (2.61-3.12), 2.20 (1.86-2.44) and 0.81 (0.58-0.98) on days 1, 2, 7, 14 and 28 of life, respectively. NVP C24 was not significantly different between term and preterm infants. All infants maintained NVP C24 ≥0.1 mg/L. EFV via placental transfer remained detectable in infants up to 7 days of life. CONCLUSIONS: NVP 4 mg/kg daily from birth provided adequate prophylactic concentrations during the first month of life in high-risk HIV-exposed neonates.

Tenofovir Exposure during Pregnancy and Postpartum in Women Receiving Tenofovir Disoproxil Fumarate for the Prevention of Mother-to-Child Transmission of Hepatitis B Virus.

We assessed tenofovir exposure during pregnancy and postpartum in hepatitis B virus (HBV)-infected HIV-uninfected women receiving tenofovir disoproxil fumarate (TDF) to prevent mother-to-child transmission of HBV. Data from 154 women who received TDF within a randomized controlled trial were included. Individual plasma tenofovir exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were estimated using a population pharmacokinetic approach. The estimated geometric mean tenofovir AUC0-24 was 20% (95% confidence interval [95% CI], 19 to 21%) lower during pregnancy than during postpartum; this modest reduction in the absence of HBV transmission suggests that no dose adjustment is needed.

Expedient screening for HIV-1 protease inhibitors using a simplified immunochromatographic assay.

A colloidal gold-based immunochromatographic (IC) strip test was developed and validated for the detection of HIV-1 protease (HIV-PR) activity and inhibitory effect of HIV-PR inhibitors (PIs). It is a unique 'two-step' process requiring the combination of proteolysis of HIV-PR and an immunochromatographic reaction. Monoclonal antibodies to the free C-terminus of HIV matrix protein (HIV-MA) conjugated to gold particles and a monoclonal antibody against intact and cleaved forms of the HIV-MA are immobilized on the 'Test'-line of the IC strip. Using lopinavir, a potent HIV protease inhibitor, the IC-strip was optimized to detect inhibitory activity against HIV-protease. At a lopinavir concentration of 1000ng/mL (its suggested minimum effective concentration), a HIV-PRH6 concentration of 6mg/mL and incubation period of 60min were the optimal conditions. A preliminary comparison between a validated high-performance liquid chromatography assay and the IC-strip to semi-quantify HIV protease inhibitor concentrations (lopinavir and atazanavir) demonstrated good agreement. This simplified method is suitable for the rapid screening of novel protease inhibitors for future therapeutic use. Moreover, the IC strip could also be optimized to semi-quantify PIs concentrations in plasma samples.

Pharmacokinetic interactions between artesunate-mefloquine and ritonavir-boosted lopinavir in healthy Thai adults.

BACKGROUND: Concomitant use of anti-malarial and antiretroviral drugs is increasingly frequent in malaria and HIV endemic regions. The aim of the study was to investigate the pharmacokinetic interaction between the anti-malarial drugs, artesunate-mefloquine and the antiretroviral drug, lopinavir boosted with ritonavir (LPV/r). METHODS: The study was an open-label, three-way, sequential, cross-over, pharmacokinetic study in healthy Thai adults. Subjects received the following treatments: Period 1: standard 3-day artesunate-mefloquine combination; Period 2 (2 months wash-out): oral LPV/r 400 mg/100 mg twice a day for 14 days; and, Period 3: artesunate-mefloquine and LPV/r twice a day for 3 days. Sixteen subjects (eight females) were enrolled and pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: In the presence of LPV/r, artesunate Cmax and systemic exposure were significantly increased by 45-80 %, while the metabolic ratio of dihydroartemisinin to artesunate was significantly reduced by 72 %. In addition, mefloquine Cmax and systemic exposure were significantly reduced by 19-37 %. In the presence of artesunate-mefloquine, lopinavir Cmax was significantly reduced by 22 % but without significant change in systemic drug exposure. The 90 % CI of the geometric mean ratio (GMR) of AUC0-∞ and Cmax were outside the acceptable bioequivalent range for each drug. Drug treatments were generally well tolerated with no serious adverse events. Vertigo, nausea and vomiting were the most common adverse events reported. CONCLUSION: The reduction in systemic exposure of all investigated drugs raises concerns of an increased risk of treatment failure rate in co-infected patients and should be further investigated.

Pharmacokinetic Interactions Between Quinine and Lopinavir/Ritonavir in Healthy Thai Adults.

This study aimed to investigate the pharmacokinetic interactions between quinine and lopinavir boosted with ritonavir (LPV/r) in healthy Thai adults (8 males and 12 females). Period 1 (day 1): subjects received a single oral dose of 600 mg quinine sulfate. Period 2: subjects received LPV/r (400/100 mg) twice daily. Period 3: subjects received a single quinine sulfate dose plus LPV/r twice a day. Intensive blood sampling was performed during each phase. Quinine AUC0-48h (area under the plasma concentration-time curve from time 0 to 48 hours), AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity), and Cmax (maximum concentration over the time-span specified), were 56%, 57%, and 47% lower, respectively, in the presence of LPV/r. 3-Hydroxyquinine AUC0-48h, AUC0-∞, and Cmax were significantly lower and the metabolite-to-parent ratio was significantly reduced. Lopinavir and ritonavir exposures were not significantly reduced with quinine coadministration, but Cmax of both drugs were significantly lower. The geometric mean ratio (GMR) and 90% CI of AUC0-48h, AUC0-∞, and Cmax for quinine, 3-hydroxyquinine, lopinavir, and ritonavir lay outside the bioequivalent range of 0.8-1.25. Drug treatments during all periods were generally well tolerated. The reduction in systemic exposure of quinine and 3-hydroxyquinine with concomitant LPV/r use raises concerns of suboptimal exposure. Studies in HIV/malaria coinfection patients are needed to determine the clinical impact to decide if any change to the quinine dose is warranted.

Plasma and Intracellular Pharmacokinetics of Tenofovir Disoproxil Fumarate 300 mg Every 48 Hours vs 150 mg Once Daily in HIV-Infected Adults With Moderate Renal Function Impairment.

BACKGROUND: The approved tenofovir disoproxil fumarate (TDF) dose of 300 mg every 48 hours for adults with moderate renal impairment is often confusing and inconvenient. Using a new TDF formulation, we compared the pharmacokinetics of the standard dose with a dose of 150 mg once daily in HIV-infected adults. METHODS: This was an open-label pharmacokinetic study. Virologically suppressed HIV-infected adults with a creatinine clearance 30 to <50 mL/minute receiving TDF 300 mg every 48 hours as part of a nonnucleoside reverse transcriptase inhibitor (NNRTI)- or lopinavir/ritonavir (LPV/r)-based regimen were enrolled. Intensive 48-hour blood sampling for pharmacokinetic assessment was performed at enrollment, after which the TDF dose was changed to 150 mg once daily. Two weeks later, 24-hour blood sampling was performed; subjects then returned to the standard dose. Tenofovir (TFV) pharmacokinetic parameters were calculated using a noncompartmental analysis. RESULTS: Forty adults (55% female) were enrolled: 20 receiving NNRTI-based and 20 receiving LPV/r-based treatment. Median age was 56 years (range, 44-65 years), weight 51 kg (range, 38-80 kg), and creatinine clearance 43.9 mL/minute (range, 30.9-49.7 mL/minute). The TFV geometric mean ratio of the area under the curve (AUC0-48 h) for every 24 hours vs every 48 hours was 1.09 (90% confidence interval [CI], .98-1.22) and 1.00 (90% CI, .92-1.09) for patients receiving NNRTI- and LPV/r-based treatment, respectively. Concomitant LPV/r use markedly increased TFV plasma concentrations, and AUC0-48 h was 67% higher with the standard dose, whereas no differences in intracellular TFV diphosphate concentrations were observed. All subjects remained virologically suppressed, and no drug-related adverse events were reported. CONCLUSIONS: TDF 150 mg every 24 hours provides comparable systemic exposure to the standard dose of 300 mg every 48 hours in patients with moderate renal impairment. CLINICAL TRIALS REGISTRATION: NCT01671982.

Pharmacogenetic markers of CYP2B6 associated with efavirenz plasma concentrations in HIV-1 infected Thai adults.

AIMS: To investigate the frequency of CYP2B6 polymorphisms and the influence of haplotype structure on plasma efavirenz concentrations in Thai adults with HIV-1 infection. METHODS: Genotyping of nine single nucleotide polymorphisms (SNPs, c.64C>T, c.499C>G, c.516G>T, c.785A>G, c.1375A>G, c.1459C>T, g.3003T>C, g.18492C>T and g.21563C>T) of CYP2B6 were performed using real-time PCR-based allelic discrimination on blood samples from 52 HIV-infected adults who had received an efavirenz-based regimen. Plasma efavirenz concentrations were measured by high performance liquid chromatography. RESULTS: The minor allele frequencies for c.64C>T, c.516G>T, c.785A>G, g.3003C>T, g.18492T>C and g.21563C>T were 0.087, 0.365, 0.413, 0.308 and 0.356, respectively. However, no variant alleles were identified for three SNPs (c.499 C>G, c.1375 A>G and c.1459 C>T). Efavirenz plasma concentrations were significantly associated with c.516G>T (P= 0.0095), c.785A>G (P= 0.0017), g.21563C>T (P= 0.0036) and g.18492C>T (P= 0.0011). The composite CYP2B6 of three SNPs (c.516G ≥ T, c.785A ≥ G and g.21563C ≥ T) genotypes were significantly associated with higher efavirenz concentrations. CONCLUSIONS: Our data indicate that the GAC-CYP2B6 haplotype is associated with higher plasma efavirenz concentrations in HIV-infected Thai adults.

Influence of CYP2B6 polymorphisms on the persistence of plasma nevirapine concentrations following a single intra-partum dose for the prevention of mother to child transmission in HIV-infected Thai women.

OBJECTIVES: To investigate the association of single nucleotide polymorphisms (SNPs) with nevirapine concentrations following intra-partum single-dose nevirapine. METHODS: Plasma and DNA samples were obtained from 330 HIV-infected Thai women who received intra-partum single-dose nevirapine in the PHPT-2 clinical trial to prevent perinatal HIV transmission. Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped by real-time PCR. Nevirapine plasma concentrations were determined by HPLC and used in a population pharmacokinetic analysis. RESULTS: Higher nevirapine exposure was observed in women carrying the CYP2B6 516G>T polymorphism, but this did not reach statistical significance (P = 0.054). The TGATC CYP2B6 haplotype (g.3003T, 516G, 785A, g.18492T and g.21563C) was associated with increased nevirapine clearance and lower exposure (P = 0.0029). The median time for nevirapine concentrations to reach 10 ng/mL post-partum (nevirapine IC(50) for HIV-1) was 14 days [interquartile range (IQR, 14-18)] for TGATC homozygotes, 16 days (14-20) for TGATC heterozygotes and 18 days (14-20) for non-TGATC homozygotes (P = 0.020). CONCLUSIONS: The CYP2B6 516G>T impact on nevirapine concentrations was less pronounced after intra-partum single-dose nevirapine than reported under steady-state conditions, perhaps due to lack of enzyme auto-induction at the time of dosing. Although the TGATC CYP2B6 haplotype may shorten the persistence of nevirapine post-partum, its practical implications for the prevention of HIV transmission or selection of resistance mutations are likely limited.

Comparison of the TaqMan and LightCycler systems in evaluation of CYP2B6 516G>T polymorphism.

Understanding genetically encoded inherited differences in drug metabolism and drug targets offers the promise of minimizing adverse drug reactions and improving therapies. We have compared two real-time PCR-based methods, the TaqMan and LightCycler for the pharmacogenetic evaluation of CYP2B6 516G>T polymorphism. Both methods were found to be suitable for pharmacogenetic testing of CYP2B6 516G>T in the meaning of time consumption, accurate genotype calling, flexible reaction format, simple data analysis, and low cost per assay. The genotype success rate was similar, but the LightCycler procedure was less expensive in terms of cost per sample and shorter running time.

Immunochromatographic strip test for rapid detection of nevirapine in plasma samples from human immunodeficiency virus-infected patients.

We report a novel one-step immunochromatographic strip test for the rapid, qualitative detection of nevirapine in plasma samples from human immunodeficiency virus-infected patients. The sensitivity was 100% (95% confidence interval [95% CI], 97.8 to 100%), and the specificity was 99.5% (95% CI, 97.2 to 99.9%). The limit of detection was 25 ng/ml. Immunochromatographic strip tests are simple, rapid, and cheap assays that could greatly facilitate drug level monitoring in resource-limited settings.