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- Chala, A, et al.
(författare)
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Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study
- 2021
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Ingår i: Journal of personalized medicine. - : MDPI AG. - 2075-4426. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- (1) Background: Efavirenz plasma concentration displays wide between-patient variability partly due to pharmacogenetic variation and autoinduction. Pediatric data on efavirenz pharmacokinetics and the relevance of pharmacogenetic variation are scarce, particularly from sub-Saharan Africa, where >90% of HIV-infected children live and population genetic diversity is extensive. We prospectively investigated the short- and long-term effects of efavirenz auto-induction on plasma drug exposure and the influence of pharmacogenetics among HIV-infected Ethiopian children. (2) Method: Treatment-naïve HIV-infected children aged 3–16 years old (n = 111) were enrolled prospectively to initiate efavirenz-based combination antiretroviral therapy (cART). Plasma efavirenz concentrations were quantified at 4, 8, 12, 24, and 48 weeks of cART. Genotyping for CYP2B6, CYP3A5, UGT2B7, ABCB1, and SLCO1B1 common functional variant alleles was performed. (3) Results: The efavirenz plasma concentration reached a peak at two months, declined by the 3rd month, and stabilized thereafter, with no significant difference in geometric mean over time. On average, one-fourth of the children had plasma efavirenz concentrations ≥4 µg/mL. On multivariate analysis, CYP2B6*6 and ABCB1c.3435 C > T genotypes and low pre-treatment low-density lipoprotein (LDL) were significantly associated with higher plasma efavirenz concentration regardless of treatment duration. Duration of cART, sex, age, nutritional status, weight, and SLCO1B, CYP3A5, UGT2B7, and ABCB1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and CYP2B6*6 and ABCB1c.3435 C > T genotypes predict efavirenz plasma exposure among HIV-infected children, but treatment-duration-dependent changes in plasma efavirenz exposure due to auto-induction are not statistically significant.
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- Kitabi, EN, et al.
(författare)
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Long-term efavirenz pharmacokinetics is comparable between Tanzanian HIV and HIV/Tuberculosis patients with the same CYP2B6*6 genotype
- 2018
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 16316-
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Tidskriftsartikel (refereegranskat)abstract
- The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as contradictory reports exist, and the relevance of CYP2B6*6 genetic polymorphism on efavirenz clearance while on-and-off anti-tuberculosis co-treatment is not well investigated. We investigated the determinants of long-term efavirenz pharmacokinetics by enrolling HIV (n = 20) and HIV/Tuberculosis (n = 36) subjects undergoing efavirenz and efavirenz/rifampicin co-treatment respectively. Pharmacokinetic samplings were done 16 weeks after initiation of efavirenz-based anti-retroviral therapy and eight weeks after completion of rifampicin-based anti-tuberculosis treatment. Population pharmacokinetic modeling was used to characterize variabilities and covariates of efavirenz pharmacokinetic parameters. CYP2B6*6 genetic polymorphism but not rifampicin co-treatment was the statistically significant covariate. The estimated typical efavirenz clearance in the HIV only subjects with the CYP2B6*1/*1 genotype was 23.6 L/h/70 kg, while it was 38% and 69% lower in subjects with the CYP2B6*1/*6 and *6/*6 genotypes, respectively. Among subjects with the same CYP2B6 genotypes, efavirenz clearances were comparable between HIV and HIV/Tuberculosis subjects. Typical efavirenz clearances before and after completion of anti-tuberculosis therapy were comparable. In conclusion, after 16 weeks of treatment, efavirenz clearance is comparable between HIV and HIV/Tuberculosis patients with the same CYP2B6 genotype. CYP2B6 genotyping but not anti-tuberculosis co-treatment should guide efavirenz dosing to optimize treatment outcomes.
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- Mnkugwe, RH, et al.
(författare)
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Optimal single sampling time-point for monitoring of praziquantel exposure in children
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 17955-
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Tidskriftsartikel (refereegranskat)abstract
- Praziquantel pharmacokinetics studies in schistosomiasis infected children are scarce partly due to the challenges/complexity of intensive blood sampling in the target population. This study was aimed to investigate the optimal single sampling time-point for monitoring praziquantel exposure. This was intensive pharmacokinetic study conducted among 32 Schistosoma mansoni infected children treated with an oral standard single-dose 40 mg/kg praziquantel. Plasma samples were collected at 0, 1, 2, 4, 6 and 8 h post-praziquantel administration. Quantification of praziquantel and its enantiomers (R- and S-praziquantel) concentrations was done by Liquid chromatography-tandem mass spectrometer (LC–MS/MS). The correlation between area under the plasma concentration–time curve from 0 to 8 h (AUC8) and plasma concentrations at each specific sampling time-point was determined by Pearson’s correlation coefficient (r2). The median age (range) of the study population was 12.5 years (10–17). The study participants were 17 males and 15 females. Both total praziquantel and its enantiomers (R- and S-praziquantel) displayed a wide inter-individual pharmacokinetic variability. Regression analysis indicated that, plasma concentrations collected at 4 h post-dose had a significantly highest correlation with the AUC8 for both total praziquantel (r2 = 0.81, p < 0.001) and S-praziquantel (r2 = 0.84, p < 0.001) than any other sampling time-point; while for R-praziquantel, plasma concentrations collected at 6 h sampling time-point had a significantly highest correlation with the AUC8 (r2 = 0.79, p < 0.001) than any other sampling time-point. Four hours sampling time-point post-praziquantel administration is ideal optimal single sampling time-point for therapeutic monitoring of total praziquantel exposure while 6 h sampling time-point is suitable for monitoring of a pharmacologically active R-praziquantel enantiomer.
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