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The influence of composite CYP2B6*6/*18 genotype on trough plasma nevirapine levels, HIV RNA levels (virologic response) and CD4+ T lymphocyte and absolute lymphocyte counts (immunologic response) of HIV-infected patients were evaluated. Patients with records of trough plasma nevirapine levels, CD4+ T lymphocyte, absolute lymphocyte and viral load counts at baseline and months 6 and 12 after initiation of nevirapine-based antiretroviral therapy combinations were retrospectively analysed. Participants were from a cohort of 150 patients previously genotyped and with measured plasma nevirapine levels. Relationship between genotype and nevirapine levels, absolute lymphocyte and CD4+ T lymphocyte counts and viral load were explored. Composite CYP2B6*6/*18 genotype was significantly associated with trough plasma nevirapine levels (geometric mean [standard deviation]: 4482 ng/ml [1349] of normal metabolizers vs. 4632 ng/ml [1793] of intermediate metabolizers vs. 6229 ng/ml [2549] of poor metabolizers; P < 0.001), but not the plasma HIV RNA levels, absolute lymphocyte and CD4+ T lymphocyte counts. Overall, immunologic response showed improvement with approximately 61.3% and 70.4% of patients with CD4+ T lymphocyte count >350 cells/mm 3 at months 6 and 12 therapy duration respectively compared to 23.1% at baseline. Composite CYP2B6*6/*18 genotype correlated with plasma nevirapine levels but not immunologic and virologic responses., (© 2022 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Aim: We aimed to assess the effect of a functional polymorphism of CYP3A5 on lumefantrine pharmacokinetics. Patients & methods: Sixty-nine women diagnosed with malaria received standard doses of artemether-lumefantrine. Concentration-time data for lumefantrine and genotyping data were obtained for each participant. Pharmacokinetic-genotype associative relationships were assessed using linear regressions, Mann-Whitney U-test or Kruskal-Wallis statistics. Results: Average age and weight (standard deviation) of the patients were 33 (6.8) years and 59.5 (11.6) kg, respectively. CYP3A5*3  genotype associated with the log-transformed maximum concentration with the median (interquartile range) values of 8279 (6516-13,420) and 6331 (4093-8631) ng/ml (p = 0.032) among the carriers and noncarriers of CYP3A5*3 , respectively. Besides, the NR1I3 c.152-1089T>C genotypes had an associative trend with the lumefantrine area under the curve (AUC 0-96h ) and clearance. Conclusion: CYP3A5 *3 genetic variant is associated with a high maximum plasma concentration of lumefantrine. This warrants further investigations on the association between CYP3A5*3 gene variants, lumefantrine pharmacokinetics and electrophysiological effect.

Estrogen-receptor positivity in tumour, often requiring long-term tamoxifen therapy, is thought to characterise between 43% and 65% of breast cancer cases in Nigeria. The patient population is further marked by late-stage diagnosis which significantly heightens the tendency for tumour relapse in the course of tamoxifen therapy. Despite tamoxifen being considered a reliable chemopreventive in high-risk individuals and an effective adjuvant therapy for hormone-sensitive tumours, mortality has remained high among breast cancer patients in the West African region where Nigeria belongs. The Nigerian breast cancer population, like other similar patient-populations in the West African region, provides a mix of intrinsic genome-diversity and perhaps unique tumour biology and evolution. These peculiarities suggest the need for a rational approach to tumour management and a personalised delivery of therapy in Nigeria's dominant estrogen-receptor-positive patient population. Herein, critical indices of tamoxifen-therapy success are discussed in the context of the Nigerian breast cancer population with emphasis on salient aspects of tamoxifen-biotransformation, host- and tumour-genomics, and epigenetics., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Adehin et al.)

Access to good-quality medicines remains a contentious issue in developing countries. This development is worrisome, particularly in a setting with a high incidence of malaria. Monitoring of antimalarial drugs in the commercial domain becomes necessary; thus, we evaluated the quality of artemether injection marketed in Southwest Nigeria. A cross-sectional survey was conducted to obtain 22 different brands of artemether injections within Southwest Nigeria. The samples were examined for their sources, lot numbers, containers for injection, oil base used for preparation, and dates of expiration. Further analysis involved visual inspection, assessment of extractable volume, identity tests, and an assay of active pharmaceutical ingredient. The pharmaceutical quality of each sample was determined according to the criteria set in the International Pharmacopoeia 2019. None of the products had any particulate matter, but there were certain irregularities in their presentation. Eighteen of the 22 products (81.7%) were packaged in plain instead of amber-colored ampoules, and 77.3% (17/22) did not indicate the oil base used as the vehicle on the label as against the pharmacopoeial standard. Sixteen products (72.7%) passed the extractable volume test, although the remaining 22.3% did not conform to the extractable volume per unit dose. Artemether was present in all the samples, although only 40.9% (9/22) met the recommended percentage content of 90-110% of artemether. The study revealed the presence of a high percentage of substandard artemether injection products marketed in Nigeria. Further surveillance is warranted to confirm the quality of artemether injection circulated in other regions within Nigeria.

Antiretroviral fixed-dose-combination drugs are best assayed with high-performance liquid chromatography, or liquid chromatography-tandem mass spectrometry. However, most scientists in developing nations have no access to these expensive instruments. A more affordable quantitative technique is the use of ultraviolet-visible spectroscopy-where often the absorption spectra of these antiretrovirals are overlapping; thus complex derivative methodologies are required for quantification. A simple, rapid, and accurate thin layer chromatography-ultraviolet spectrophotometric method for the quantification of binary mixtures of lamivudine, zidovudine, and tenofovir-disoproxil-fumarate in tablet formulations was developed. Lamivudine/tenofovir-disoproxil-fumarate and lamivudine/zidovudine were extracted and separated on glass thin-layer chromatography plates. Drugs were identified in ultraviolet light at 254 nm and quantified in acidic medium using ultraviolet spectrophotometry. The retardation factors were 0.43, 0.79, and 0.81 for lamivudine, tenofovir-disoproxil-fumarate, and zidovudine, respectively, with corresponding absorption maxima at 270, 260, and 265 nm. Linearity ranged from 1 to 40 µg/mL for all drugs (R = 0.9998-0.9999), while recovery studies were 95.10-102.11% and amount in formulations ranged from 97.99 ± 0.63 to 101.47 ± 2.39%. The paired t-test (n = 5) indicated no significant difference between the proposed and high-performance liquid chromatography methods, hence comparable and can be used as an alternative method in routine quality determination of antiretroviral medicines., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of CYP2B6*6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers-15 noncarriers (CYP2B6*1/*1) and 15 homozygote carriers (CYP2B6*6/*6)-selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3-day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampling was conducted at different time points before and after the last dose. Plasma concentrations of artemether, lumefantrine, dihydroartemisinin, and desbutyllumefantrine were quantified using validated liquid chromatography-mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of CYP2B6*6/*6 volunteers was nonsignificantly lower by 26% (ratios of geometric mean [90% CI]; 0.74 [0.52-1.05]), and total exposure (the area under the plasma concentration-time curve from time 0 to infinity [AUC 0-∞ ]) was greater by 35% (1.35 [0.95-1.93]) when compared with those of *1/*1 volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC 0-∞ was 22% lower. On the contrary, artemether-to-dihydroartemisinin AUC 0-∞ ratio was 73% significantly higher (1.73 [1.27-2.37]). Comparison of lumefantrine exposure and lumefantrine-to-desbutyllumefantrine metabolic ratio of *6/*6 with corresponding data from *1/*1 volunteers showed no differences. The increased artemether-to-dihydroartemisinin metabolic ratio of *6/*6 volunteers is unlikely to result in differences in artemether-lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate CYP2B6*6 genotype with artemether disposition., (© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes, were administered a complete treatment dose of 3 days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted, and the plasma concentrations of artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry. Pharmacokinetic parameters of artemether-lumefantrine and its metabolites in HIV-infected patients on nevirapine were compared to those in the absence of nevirapine in HIV-negative volunteers. Overall, nevirapine reduced exposure to artemether and desbutyl-lumefantrine by 39 and 34%, respectively. These reductions were significantly greater in GG versus TT subjects for artemether (ratio of geometric mean [90% confidence interval]: 0.42 [0.29 to 0.61] versus 0.81 [0.51 to 1.28]) and for desbutyl-lumefantrine (0.56 [0.43 to 0.74] versus 0.75 [0.56 to 1.00]). On the contrary, it increased exposure to dihydroartemisinin and lumefantrine by 47 and 30%, respectively. These increases were significantly higher in TT versus GG subjects for dihydroartemisinin (1.67 [1.20 to 2.34] versus 1.25 [0.88 to 1.78]) and for lumefantrine (1.51 [1.20 to 1.90] versus 1.08 [0.82 to 1.42]). This study underscores the importance of incorporating pharmacogenetics into all drug-drug interaction studies with potential for genetic polymorphisms to influence drug disposition., (Copyright © 2020 Abdullahi et al.)

Background: The varied disposition of the antimalarial quinine partly explains its poor tolerance and toxicity in humans., Objective: Using a population approach, the disposition of quinine in healthy subjects and patients with acute uncomplicated symptomatic malaria from Nigeria was re-examined with a view to providing population-specific attributes., Methods: Concentration versus time profiles of quinine over 48 hours in healthy individuals, and over 7 days in malaria-infected patients, were stratified to reflect: concentration versus time data during the first 48 hours of quinine administration for healthy subjects and infected patients, concentration versus time data after 48 hours in infected patients, and all concentration versus time data available for healthy subjects and infected patients. Pharmacokinetic parameters were then estimated with a stochastic approximation expectation maximization algorithm., Results: All datasets were fitted by a 1-compartment model with covariate contributions from body weight and infection status. The absorption rate constant, and volume of distribution and clearance were 1.72 h -1 , 86.8 to 157.4 L, and 6.6 to 9.6 L/h, respectively. Infected patients experienced a 38% decrease in volume of distribution and a 31% decrease in clearance in the first 48 hours relative to healthy individuals. The contraction in volume of distribution and clearance diminished significantly after 48 hours of chronic quinine dosing in infected patients., Conclusions: The study findings suggest that clinical interventions aimed at enhancing the safety and tolerance of quinine might be achieved by a rational decrease in dose size and/or dosing interval, post-48 hours of chronic quinine administration, in malaria-infected patients., Competing Interests: The authors have indicated that they have no conflicts of interest regarding the content of this article., (© 2019 The Author(s).)

Aims: In this study the influence of first-line antimalarial drug artemether-lumefantrine on the pharmacokinetics of the antiretroviral drug nevirapine was investigated in the context of selected single nucleotide polymorphisms (SNPs) in a cohort of adult HIV-infected Nigerian patients., Methods: This was a two-period, single sequence crossover study. In stage 1, 150 HIV-infected patients receiving nevirapine-based antiretroviral regimens were enrolled and genotyped for seven SNPs. Sparse pharmacokinetic sampling was conducted to identify SNPs independently associated with nevirapine plasma concentration. Patients were categorized as poor, intermediate and extensive metabolizers based on the numbers of alleles of significantly associated SNPs. Intensive sampling was conducted in selected patients from each group. In stage 2, patients received standard artemether-lumefantrine treatment with nevirapine, and intensive pharmacokinetic sampling was conducted on day 3., Results: No clinically significant changes were observed in key nevirapine pharmacokinetic parameters, the 90% confidence interval for the measured changes falling completely within the 0.80-1.25 no-effect boundaries. However, the number of patients with trough plasma nevirapine concentration below the 3400 ng ml -1 minimum effective concentration increased from 10% without artemether-lumefantrine (all extensive metabolizers) to 21% with artemether-lumefantrine (14% extensive, 4% intermediate, and 3% poor metabolizers)., Conclusions: This approach highlights additional increase in the already existing risk of suboptimal trough plasma concentration, especially in extensive metabolizers when nevirapine is co-administered with artemether-lumefantrine., (© 2018 The British Pharmacological Society.)

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., (Copyright © 2018 American Society for Microbiology.)

This study evaluated the effects of concurrent ciprofloxacin administration on the disposition of quinine in healthy volunteers. Quinine (600-mg single dose) was administered either alone or with the 11th dose of ciprofloxacin (500 mg every 12 hours for 7 days) to 15 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analyzed for quinine and its major metabolite, 3-hydroxquinine, using a validated high-performance liquid chromatographic method. Administration of quinine plus ciprofloxacin resulted in significant increases (P < 0.05) in the total area under the concentration-time curve, maximum plasma concentration (Cmax), and terminal elimination half-life (T1/2b) of quinine compared with values with quinine dosing alone (AUC: 27.93 ± 8.04 vs. 41.62 ± 13.98 h·mg/L; Cmax: 1.37 ± 0.24 vs. 1.64 ± 0.38 mg/L; T1/2b: 16.28 ± 2.66 vs. 21.43 ± 3.22 hours), whereas the oral plasma clearance markedly decreased (23.17 ± 6.49 vs. 16.00 ± 5.27 L/h). In the presence of ciprofloxacin, there was a pronounced decrease in the ratio of AUC (metabolite)/AUC (unchanged drug) and highly significant decreases in Cmax and AUC of the metabolite (P < 0.05). Ciprofloxacin may increase the adverse effects of concomitantly administered quinine, which can have serious consequences on the patient. Thus, a downward dosage adjustment of quinine seems to be necessary when concurrently administered with ciprofloxacin.

Objectives: The validation and clinical application of an LC-MS/MS method for the quantification of nevirapine in dried blood spots (DBS) and dried breast-milk spots (DBMS) are presented., Methods: DBS and DBMS were prepared from 50 and 30 μL of nevirapine-spiked whole blood and human breast milk, respectively. Chromatographic separation was achieved on a reverse-phase C18 column with 0.1% formic acid in water/acetonitrile using a solvent gradient programme at a flow rate of 400 μL/min, and detection was by a TSQ Quantum Access triple quadrupole mass spectrometer. The clinical application was evaluated in HIV-positive nursing mothers and their breastfed infants., Results: The assay was validated over the concentration range 50-10,000 ng/mL. Accuracy ranged from 93.3% to 113.4% and precision ranged from 1.9% to 12.0%. The mean (percentage coefficient of variation) recovery of nevirapine from DBS and DBMS was ≥ 70.7% (≤ 8.2) and the matrix effect was ≤ 1.04 (≤ 6.1). Nevirapine was stable in DBS and DBMS for ≥ 15 months at room temperature and -80°C. Mean (SD) AUC0-12, Cmax and Cmin in maternal plasma versus breast milk were 57,808 ng · h/mL (24,315) versus 55,817 ng · h/mL (22,368), 6140 ng/mL (2605) versus 5231 ng/mL (2215) and 4334 ng/mL (1880) versus 4342 ng/mL (2245), respectively. The milk-to-plasma concentration ratio over the dosing interval was 0.94 (0.15). Infant plasma concentrations 2 and 8 h after maternal dosing were 580.6 ng/mL (464.7-1607) and 584.1 ng/mL (381.5-1570), respectively., Conclusions: These methods further extend opportunities for conducting clinical pharmacokinetic studies in nursing mother-infant pairs, especially in resource-limited settings., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We investigated the effect of concurrent ingestion of Garcinia kola seed on the pharmacokinetics of quinine. In a randomized crossover study, 24 healthy Nigerian volunteers were assigned into 2 groups (A and B; n = 12 per group) on the basis of G. kola dose orally ingested. Each subject received 600 mg quinine sulfate before and after ingesting 12.5 g of G. kola once daily for 7 days (group A) or 12.5 g twice daily for 6 days and once on the seventh day (group B). Blood samples were collected and analyzed for plasma quinine and its metabolite (3-hydroxyquinine) using a validated high performance liquid chromatography method. Concurrent administration of quinine with G. kola reduced quinine tmax by 48% (group A), mean Cmax by 19% and 26% in groups A and B, respectively, and slight reduction in mean AUC0- ∞ of quinine in both groups. 3-hydroxyquinine Cmax also reduced by 29% and 32%; AUC0-∞ by 13% and 9%, respectively. The point estimates of the T/R ratio of the geometric means for all Cmax obtained and only the AUC0-∞ at a higher dose of G. kola were outside the 80%-125% bioequivalence range. In conclusion, an herb-drug interaction was noted with concurrent quinine and G. kola administration., (© 2014, The American College of Clinical Pharmacology.)

The naked mole-rat possesses several unique physiological and molecular features that underlie their remarkably and exceptional resistance to tissue hypoxia. Elevated pattern of Epo, an erythropoietin (Epo) factor; c-fos; vascular endothelial growth factor (VEGF); and hypoxia-inducible factors (HIF-1α) contribute to the adaptive strategy to cope with hypoxic stress. Moreover, the naked mole-rat has a lower metabolic rate than any other eutherian mammal of comparable size that has been studied. The ability to actively reduce metabolic rate represents a strategy widely used in the face of decreased tissue oxygen availability. Understanding the different molecular and physiological factors that induce metabolic suppression could guide the development of pharmacological agents for the clinical management of stroke patient.

Objectives: This manuscript describes the development, validation and clinical application of a novel method for the quantification of the antiretroviral drug efavirenz in dried breast milk spots using LC-MS., Methods: Dried breast milk spots were prepared by spotting 30 μL of human breast milk on each circle of Whatman 903 Protein Saver cards. Chromatographic separation was achieved on a reverse-phase C18 column with 1 mM ammonium acetate in water/acetonitrile using a solvent gradient at a flow rate of 400 μL/min and detection was by TSQ Quantum Access triple quadrupole mass spectrometer equipped with a heated electrospray ionization source. The method was applied to characterize the breast milk pharmacokinetic profile of efavirenz in HIV-positive nursing mothers receiving regimens containing 600 mg of efavirenz once daily., Results: The assay was validated over the concentration range 50-7500 ng/mL. Accuracy ranged between 95.2% and 102.5% and precision ranged between 1.05% and 9.53%. The average recovery of efavirenz from dried breast milk spots was 106.4% and the matrix effect was 8.14%. Stability of efavirenz in dried breast milk spots and processed samples at room temperature, -40°C and -80°C was demonstrated. In the pharmacokinetic study, the mean (SD) AUC0-24, Cmax and Cmin of efavirenz in breast milk were 59,620 ng·h/mL (17,440), 4527 ng/mL (1767) and 1261 ng/mL (755.9), respectively. The mean (range) milk-to-plasma concentration ratio over the dosing interval was 0.78 (0.57-1.26)., Conclusions: The dried breast milk spot method is simple, robust, accurate and precise, and can be used in settings with limited resources., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Recent investigations of hypoxia physiology in the naked mole rat have opened up an interesting line of research into the basic physiological and genomic alterations that accompany hypoxia survival. The extent to which such findings connect the effect of hypoxia to metabolic rate (O₂ consumption), core body temperature (Tb), and transcripts encoding the immediate early gene product (such as c-fos) under a constant ambient temperature (Ta) is not well known. We investigated this issue in the current study. Our first sets of experiments measured Tb and metabolic rates during exposure of naked mole rats to hypoxia over a constant Ta. Hypoxia significantly decreased metabolic rates in the naked mole rat. Although core Tb also decreased during hypoxia, the effect of hypoxia in suppressing core Tb was not significant. The second series of experiments revealed that c-fos protein and mRNA expression in the hippocampus neurons (CA1) increased in naked mole rats that were repeatedly exposed to 3% O₂ for 60 min per day for 5 days when compared to normoxia. Our findings provide evidence for the up-regulation of c-fos and suppression of metabolic rate in hypoxia tolerating naked mole rats under constant ambient temperature. Metabolic suppression and c-fos upregulation constitute part of the physiological complex associated with adaptation to hypoxia., (Published by Elsevier Ltd.)

Aims: To evaluate the pharmacokinetic interactions between ritonavir and quinine in healthy volunteers., Methods: Ten healthy volunteers were each given 600-mg single oral doses of quinine alone, ritonavir alone (200 mg every 12 h for 9 days), and quinine in combination with ritonavir, in a three-period pharmacokinetic nonrandomized sequential design study. Quinine was co-administered with the 15th dose of ritonavir. Blood samples collected at predetermined time intervals were analysed for ritonavir, quinine and its major metabolite, 3-hydroxyquinine, using a validated high-performance liquid chromatography method., Results: Concurrent ritonavir administration resulted in about fourfold increases in both the C(max) and AUC(T)[C(max) 2.79 +/- 0.22 vs. 10.72 +/- 0.32 mg l(-1), 95% confidence interval (CI) 7.81, 8.04; AUC 50.06 +/- 2.52 vs. 220.47 +/- 6.68 mg h(-1) l(-1), 95% CI 166.3, 175.3], a significant increase (P < 0.01) in the elimination half-life (11.15 +/- 0.80 vs. 13.37 +/- 0.33 h, 95% CI 1.64, 2.77) and about a 4.5-fold decrease in CL/F (12.01 +/- 0.61 vs. 2.71 +/- 0.09 l h(-1)) of quinine. Also, with ritonavir, there was a pronounced reduction of AUC(metabolite)/AUC(unchanged drug) ratio of quinine (1.35 +/- 0.10 vs. 0.13 +/- 0.02) along with a marked decrease in C(max) (1.80 +/- 0.12 vs. 0.96 +/- 0.09 mg l(-1)) and AUC(0-48h) (62.80 +/- 6.30 vs. 25.61 +/- 2.44 mg h(-1) l(-1)) of the metabolite. Similarly, quinine caused modest but significant increases (P < 0.01) in the C(max), AUC and elimination T((1/2)) of ritonavir., Conclusions: Downward dosage adjustment of quinine appears necessary when concurrently administered with ritonavir.

Efavirenz and proguanil are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of proguanil is mediated principally by CYP2C19 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on proguanil disposition. Fifteen healthy volunteers were each given 300 mg single oral doses of proguanil alone or with the 9th dose of efavirenz (400mg daily for 11 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for proguanil and its major metabolite, cycloguanil, using a validated HPLC method. Co-administration of proguanil and efavirenz resulted in significant increases (p < 0.05) in C(max), T(max), AUC(T) and elimination half-life (T(1/2beta)) of proguanil compared with values for proguanil alone [C(max): 2.55+/-0.24 mg/l vs 3.75+/-0.48 mg/l; T(max): 2.80+/-0.99 h vs 4.80+/-0.99 h; AUC(T): 45.58+/-12.75 mgh/l vs 97.00+/-23.33 mgh/l; T(1/2beta): 16.50+/-4.55 h vs 23.24+/-4.08 h]. Also, efavirenz caused a pronounced decrease in the AUC(metabolite)/AUC(unchanged drug) ratio of proguanil along with a significant decrease (p < 0.05) in C(max) and AUC of the metabolite. These results indicate that efavirenz significantly alters the pharmacokinetics of proguanil. These suggest that the protection against malaria by proguanil may be decreased when the drug is co-administered with efavirenz and the antimalarial efficacy is dependent on cycloguanil plasma levels., (2009 Elsevier B.V. All rights reserved.)

Objectives: Nevirapine and quinine are likely to be administered concurrently in the treatment of patients with HIV and malaria. Both drugs are metabolised to a significant extent by cytochrome P450 (CYP)3A4 and nevirapine is also an inducer of this enzyme. This study therefore evaluated the effect of nevirapine on the pharmacokinetics of quinine., Methods: Quinine (600 mg single dose) was administered either alone or with the 17th dose of nevirapine (200 mg every 12 h for 12 days) to 14 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analysed for quinine and its major metabolite, 3-hydroxquinine, using a validated HPLC method., Key Findings: Administration of quinine plus nevirapine resulted in significant decreases (P < 0.01) in the total area under the concentration-time curve (AUC(T)), maximum plasma concentration (C(max)) and terminal elimination half-life (T((1/2)beta)) of quinine compared with values with quinine dosing alone (AUC: 53.29 +/- 4.01 vs 35.48 +/- 2.01 h mg/l; C(max): 2.83 +/- 0.16 vs 1.81 +/- 0.06 mg/l; T((1/2)beta): 11.35 +/- 0.72 vs 8.54 +/- 0.76 h), while the oral plasma clearance markedly increased (11.32 +/- 0.84 vs 16.97 +/- 0.98 l/h). In the presence of nevirapine there was a pronounced increase in the ratio of AUC(metabolite)/AUC (unchanged drug) and highly significant increases in C(max) and AUC of the metabolite (P < 0.01)., Conclusions: Nevirapine significantly alters the pharmacokinetics of quinine. An increase in the dose of quinine may be necessary when the drug is co-administered with nevirapine.

In regions with high prevalence of HIV and malaria, co-infection of both diseases is common; hence, there is a high possibility of concurrent administration of antiretroviral and antimalarial drugs. This study describes a new ion-pair reversed-phase high-performance liquid chromatographic (HPLC) method for simultaneous determinations of ritonavir (RTV), quinine (QN), and its major metabolite, 3-hydroxyquinine (3-HQN), in human plasma. Following a simple extraction with diethyl-ether under alkaline conditions, chromatographic separation was achieved on a 5-mum particle size C-18 column (200 mm x 4.6mm I.D.) using a mobile phase consisting of methanol:acetonitrile:0.02 M potassium dihydrogen phosphate (15:10:75) containing 75 mmol/L perchloric acid (pH 2.8). Retention times for RTV, 3-HQN, QN and the internal standard were 2.8, 4.0, 7.0 and 12 min, respectively. The limits of detection and validated lower limits of quantitation were 10 and 12.5 ng/ml for RTV while the corresponding values were 5 and 70 ng/ml for both QN and 3-HQN, respectively. The new HPLC method is simple, rapid, selective, reproducible and cost-effective. As demonstrated in three volunteers, it will facilitate the conducting of simultaneous therapeutic monitoring of quinine and ritonavir in patients concurrently receiving both drugs.