Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

BACKGROUND: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. CONCLUSIONS: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

Pharmacokinetic Parameters of Quinine in Healthy Subjects and in Patients with Uncomplicated Malaria in Nigeria: Analysis of Data using a Population Approach.

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.

Pharmacokinetic interactions between ritonavir and quinine in healthy volunteers following concurrent administration.

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.

Post-Marketing Surveillance of Quality of Artemether Injection Marketed in Southwest Nigeria.

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.

Simultaneous liquid chromatographic analysis of ritonavir, quinine and 3-hydroxyquinine in human plasma.

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.

Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers.

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.

Therapeutic Potentials and Cytochrome P450-Mediated Interactions Involving Herbal Products Indicated for Diabetes Mellitus.

BACKGROUND: There has been an increase in the use of herbal products to complement conventional drugs in the treatment of various diseases especially in developing countries. This may be attributable to the potential cost-effectiveness and ease of accessibility of these products as well as the perception of their safety profiles. However, there are numerous literature reports on herbs altering the pharmacokinetics and pharmacodynamics of other co-administered drugs thereby modulating the therapeutic outcomes. The prevalence of diabetes is on a steady increase worldwide and it is now identified as one of the main threats to human health. OBJECTIVE: It is important that knowledge on specific effects of antidiabetic herbs and their products on drug metabolizing enzymes are updated and documented so as to ensure optimization of their therapeutic utility. This review, therefore, aims to highlight herbal products with evidence-based antidiabetic effects, identify their bioactive phyto-constituents, and also focus on the important Cytochrome P450 and consequences of their inhibition or induction. METHODS: An extensive literature search was undertaken and the information obtained were critically analyzed and discussed. RESULTS AND CONCLUSION: The literature abounds with reports on the utilization of herbal medications for the treatment of diabetes mellitus since time immemorial, but very few of these herbal products have undergone clinical trials. Also, studies on the herb-drug interactions were limited. Due to the complex phytochemical composition of the herbs, concomitant administration with conventional drugs resulted in alterations of pharmacological effects of some drugs. Evidences of beneficial interactions were identified for medical exploitation.

Effect of dehusked Garcinia kola seeds on the overall pharmacokinetics of quinine in healthy Nigerian volunteers.

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.

Chemotherapeutic interaction between Khaya grandifoliola (WELW) CDC stem bark extract and two anti-malarial drugs in mice.

In malarial endemic countries especially in the tropics, conventional antimalarial drugs are used with herbal remedies either concurrently or successively. Khaya grandifoliola is one of such popular herbs used in the treatment of malaria.Various doses of ethanol extract of K. grandifoliola stem bark (50-400 mg/kg/day) were administered orally to Swiss albino mice infected with Plasmodium yoelii nigerense. A dose of 100 mg/kg/day of the extract was also combined with 2.5 mg/kg/day of chloroquine or 6.25 mg/kg/day of halofantrine in both early and established malaria infection test models. The results showed that in the early malaria infection test, K. grandifoliola in combination with chloroquine or halofantrine elicited enhanced antiplasmodial effect in the established infection, there was significantly greater parasite clearance following administration of the combination when compared to the effects of K. grandifoliola or the conventional drugs alone. The mean survival period of parasitized animals was also enhanced by the extract/halofantrine combination. Lower therapeutic doses of halofantrine may be required to potentiate parasite clearance when used in combination with K. grandifoliola. This may constitute great advantage to halofantrine which is associated with cardiotoxicity at high doses.

Effects of prior administration of amodiaquine on the disposition of halofantrine in healthy volunteers.

The prevalence of multidrug-resistant malaria parasites brings about the switch from an antimalarial drug with poor therapeutic outcome to an effective alternative, resulting in overlap in the plasma drug levels. In this study, the influence of prior administration of amodiaquine on the pharmacokinetics and electrocardiographic effect of halofantrine (HF) was investigated in healthy volunteers. Ten healthy male subjects were each given single oral doses of 500 mg HF alone or with 600 mg of amodiaquine hydrochloride (AQ) administered 24 hours before the HF dose in a crossover fashion. Blood samples, collected at predetermined time intervals, were analyzed for HF and its major metabolite, desbutylhalofantrine (HFM) using a validated high-performance liquid chromatography method. Electrocardiogram for each volunteer was taken at predetermined time points. Results showed that prior administration of amodiaquine resulted in no significant changes (P > 0.05) in any of the pharmacokinetic parameters of HF. For example, the parameter values for HF alone and with AQ were: Cmax 144 +/- 53 versus 164 +/- 58 microg/L; T1/2beta 142 +/- 23 versus 139 +/- 28 hours; Cl/F 37.3 +/- 13.9 versus 32.3 +/- 11.4 L/h; and metabolic ratio 1.2 +/- 0.5 vs 1.1 +/- 0.6 Similarly, the disposition of HFM was not significantly altered (P > 0.05) after an earlier exposure to amodiaquine. In addition, the presence of AQ was linked with a further lengthening of the QT interval compared with the effect of HF alone. This study suggests that prior administration of AQ does not result in a significant alteration of the pharmacokinetics of HF but may be associated with an increased risk of QT prolongation. It may be necessary to exercise caution in the use of HF for malaria treatment in persons who have recently received AQ.

Effects of tetracycline on the pharmacokinetics of halofantrine in healthy volunteers.

AIMS: To investigate the effect of tetracycline co-administration on the pharmacokinetics of halofantrine in healthy subjects. METHODS: Eight healthy males were each given 500 mg single oral doses of halofantrine alone, or with tetracycline (500 mg 12 hourly for 7 days), in a crossover fashion. Blood samples collected at predetermined intervals were analyzed for halofantrine and its major metabolite, desbutylhalofantrine (HFM), using a validated HPLC method. RESULTS: Co-administration of tetracycline and halofantrine resulted in a significant increase (P < 0.05) in the maximum plasma concentration (C(max)), total area under the concentration-time curve (AUC), and terminal elimination half-life (t(1/2,z)), compared with halofantrine alone. (C(max) 0.43 +/- 0.14 vs 1.06 +/- 0.44 microg ml(-1) (95% CI on the difference 0.30, 0.95); AUC 32.0 +/- 13.6 vs 63.7 +/- 20.1 microg ml(-1) h (95% CI 14.2, 49.1); t(1/2,z:) 90.8 +/- 17.9 vs 157.4 +/- 57.4 h (95% CI 21.7, 111.5)). Similarly, tetracycline caused a significant increase (P < 0.05) in the AUC and C(max) of HFM. CONCLUSIONS: Tetracycline co-administration significantly increases the plasma concentrations of halofantrine and its major metabolite.

Evidence for increased metabolism of chloroquine during the early third trimester of human pregnancy.

OBJECTIVE: To examine the possibility of a different extent of chloroquine (CQ) metabolism in human pregnancy by determining blood level profiles of the drug and its major metabolite, desethylchloroquine (CQM). METHODS: Five women in the early third trimester of pregnancy and five non-pregnant women received each a single 600 mg oral dose of CQ and blood samples were collected at pre-determined intervals following drug administration. Plasma concentrations of CQ and CQM were analysed by an established HPLC method. RESULTS: The C(max) and AUC(0-48 h) of CQM were significantly higher in the pregnant than the non-pregnant group (P = 0.009). The ratio AUC(CQ)/AUC(CQM) ranged from 0.09 to 0.35 among pregnant women, and from 1.70 to 4.81 among non-pregnant women. CONCLUSION: Results from this preliminary study indicate an occurrence of induction of metabolism of CQ in the early third trimester of pregnancy. In view of toxicological importance of CQ metabolites, it is suggested that caution should be exercised in evaluation of higher dosage regimen of CQ in pregnant women.