Pharmacokinetics Of Quinine Research Articles

Clinical pharmacokinetics of quinine and its relationship with treatment outcomes in children, pregnant women, and elderly patients, with uncomplicated and complicated malaria: a systematic review

BackgroundStandard dosage regimens of quinine formulated for adult patients with uncomplicated and complicated malaria have been applied for clinical uses in children, pregnant women, and elderly. Since these populations have anatomical and physiological differences from adults, dosage regimens formulated for adults may not be appropriate. The study aimed to (i) review existing information on the pharmacokinetics of quinine in children, pregnant women, and elderly populations, (ii) identify factors that influence quinine pharmacokinetics, and (iii) analyse the relationship between the pharmacokinetics and treatment outcomes (therapeutic and safety) of various dosage regimens of quinine.MethodsWeb of Sciences, Cochrane Library, Scopus, and PubMed were the databases applied in this systematic search for relevant research articles published up to October 2020 using the predefined search terms. The retrieved articles were initially screened by titles and abstracts to exclude any irrelevant articles and were further evaluated based on full-texts, applying the predefined eligibility criteria. Excel spreadsheet (Microsoft, WA, USA) was used for data collection and management. Qualitative data are presented as numbers and percentages, and where appropriate, mean + SD or median (range) or range values.ResultsTwenty-eight articles fulfilled the eligibility criteria, 19 in children, 7 in pregnant women, and 2 in elderly (14 and 7 articles in complicated and uncomplicated malaria, respectively). Severity of infection, routes of administration, and nutritional status were shown to be the key factors impacting quinine pharmacokinetics in these vulnerable groups.ConclusionsThe recommended dosages for both uncomplicated and complicated malaria are, in general, adequate for elderly and children with uncomplicated malaria. Dose adjustment may be required in pregnant women with both uncomplicated and complicated malaria, and in children with complicated malaria. Pharmacokinetics studies relevant to clinical efficacy in these vulnerable groups of patients with large sample size and reassessment of MIC (minimum inhibitory concentration) should be considered.

Evidence for treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy

Evidence for treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy

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.

Preliminary Study of Quinine Pharmacokinetics in Pregnant Women with Malaria-HIV Co-Infection

Pregnant women bear the greatest burden of malaria–human immunodeficiency virus co-infection. Previous studies suggest that interaction with antiretroviral drugs may compromise antimalarial pharmacokinetics and treatment outcomes. We conducted a preliminary clinical study to assess quinine pharmacokinetics in Malian pregnant women with acute malaria who reported taking nevirapine-based antiretroviral therapy. Of seven women, six had stable concentrations of nevirapine in the plasma and one had none. Quinine concentrations were lower, and its metabolite 3-hydroxyquinine higher, in the six women with nevirapine than in the one without, and quinine concentrations were below the recommended therapeutic range in 50% of the women. This preliminary observation warrants further research to understand the impact of long-term antiretroviral therapy on the treatment of acute malaria.

Effects of capsaicin on the pharmacokinetics of antipyrine, theophylline and quinine in rats.

Capsaicin is the active principal of capsicum fruits, such as hot peppers. The influence of 1-week pretreatment of capsaicin (25 mg kg-1) on the pharmacokinetics of antipyrine, theophylline and quinine was investigated in rats. The drugs were given as an intravenous bolus dose. The control rats received the vehicle solvent (polyethylene glycol) only. Clearance of antipyrine in the capsaicin-pretreated rats was significantly lower than that observed in the control rats (0.241 +/- 0.029 vs 0.344 +/- 0.034 L h-1 kg-1, P < 0.05). This is consistent with a prolongation in the elimination half-life of antipyrine in animals pretreated with capsaicin (2.06 +/- 0.30 vs 1.61 +/- 0.27 h), as the volume of distribution was not significantly changed. In contrast, capsaicin pretreatment had no significant effect on the pharmacokinetics of theophylline and quinine.

The Disposition of Quinine in the Rat Isolated Perfused Liver: Effect of Dose Size

We have investigated the pharmacokinetics of both free and total quinine in the rat isolated perfused liver at three doses, 6.25, 12.5 and 25 mg. The plasma concentrations of free and total quinine decayed biexponentially over 4 h. However, on increasing dose, the terminal half-life of free and total quinine showed marked increases ranging from 12.4 +/- 3.7 min at 6.25 mg to 176.0 +/- 153 min at 25 mg (total quinine). Quinine clearance was reduced approximately by half as the dose was doubled. At 10 min post dosage, quinine extraction at the 6.25 mg dose (56 +/- 16.3%) was more than twice that of the highest dose (25 mg, 25.0 +/- 6.5%). Free quinine at the 6.25 mg dose was cleared at approximately 100% of perfusate flow, whereas at 25 mg, clearance was less than one fifth of that value. Unchanged quinine elimination in bile was low, with less than 1% of the parent drug being detected at the 12.5 and 25 mg doses. Relatively little parent drug was recovered from the liver at 4 h. At the 25 mg dose, less than or equal to 6% was recovered as parent drug. HPLC analysis revealed some polar metabolites of quinine in the bile and in the liver homogenates. Dose dependent kinetics of quinine were demonstrated in this study, as hepatic extraction of quinine decreased with increasing dose and input concentration.

The Effect of Fever on Quinine and Quinidine Disposition in the Rat

The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin-induced fever in rats resulted in an increased quinine clearance (CL) (4.49 +/- 1.45 vs 1.38 +/- 0.65 L h-1 kg-1, P less than 0.001) and volume of distribution (Vd) (42.6 +/- 8.8 vs 28.9 +/- 10.3 L kg-1, P less than 0.05) with a concomitant shortening of the elimination half-life (t1/2) (7.1 +/- 2.5 vs 15.9 +/- 5.9 h, P less than 0.01). With quinidine, however, fever resulted in an increased CL (3.95 +/- 1.05 vs 1.89 +/- 0.60 L h-1 kg-1, P less than 0.002) with no change in Vd and a significant decrease in t1/2 (5.1 +/- 0.7 vs 10.1 +/- 2.8 h, P less than 0.001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In-vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense.

Effects of Plasmodium falciparum infection on the pharmacokinetics of quinine and its metabolites in pregnant and non-pregnant Sudanese women

The study aimed to investigate the effects of Plasmodium falciparum infection on the pharmacokinetics of quinine and its metabolites in pregnant and non-pregnant Sudanese women. In a case-control study, nine pregnant and eight non-pregnant Sudanese women infected with P. falciparum were treated with intramuscular artemether. Before being given artemether, they received a single dose of quinine hydrochloride as intravenous infusion. Blood samples were collected frequently and analysed for quinine and its metabolites (phase I). One week later (after clearance of parasitaemia) the quinine part of the protocol was repeated (phase II). During phase I, the AUCs (mean ± SD) of quinine and its major metaboplite, 3-hydroxyquinine, in pregnant women were 428.2 ± 132.4 and 27.8 ± 14.1μmol l(-1) h(-1) respectively. In non-pregnant women the AUCs of quinine and 3-hydroxyquinine were 517.8 ± 100.0 and 32.3 ± 15.3μmol l(-1) h(-1). In pregnant women the mean (90% confidence interval) AUC ratios of phase I to phase II of quinine and 3-hydroxyquinine were 1.6 (0.61, 4.22) and 1.01 (0.18, 5.60). In non-pregnant women, the AUC ratios of phase I to phase II of quinine and 3-hydroxyquinine were 1.93 (1.74, 2.15) and 1.19 (0.95, 1.47). Plasmodium falciparum infection significantly increased plasma concentration of quinine in non-pregnant women and showed the same trend in pregnant women.

Quinine pharmacokinetics and toxicity in African subjects

Quinine pharmacokinetics and toxicity in African subjects

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

AbstractObjectivesNevirapine 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.MethodsQuinine (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 findingsAdministration of quinine plus nevirapine resulted in significant decreases (P &amp;lt; 0.01) in the total area under the concentration–time curve (AUCT), maximum plasma concentration (Cmax) and terminal elimination half-life (T1/2β) of quinine compared with values with quinine dosing alone (AUC: 53.29 ± 4.01 vs 35.48 ± 2.01 h mg/l; Cmax: 2.83 ± 0.16 vs 1.81 ± 0.06 mg/l; T1/2β: 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 Cmax and AUC of the metabolite (P &amp;lt; 0.01).ConclusionsNevirapine significantly alters the pharmacokinetics of quinine. An increase in the dose of quinine may be necessary when the drug is co-administered with nevirapine.

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

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. 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. 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). 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.

Pharmacokinetics of quinine and its metabolites in pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria

The study was conducted in New Halfa teaching hospital, eastern Sudan to investigate the pharmacokinetics of quinine in pregnant Sudanese women. Sixteen (eight pregnant and eight non-pregnant) Sudanese women infected with Plasmodium falciparum malaria were given a single dose of quinine hydrochloride (10 mg/kg body weight) as intravenous infusion over 2 h. The women were treated with intramuscular artemether. Plasma was collected before quinine administration and up to 72 h thereafter. These were analysed for quinine and its metabolites, 3-hydroxyquinine, (10R)-10,11-dihydroxyquinine and (10S)-10,11-dihydroxyquinine using high-performance liquid chromatography. The two groups were well matched in their basic characteristics. There was no significant difference in the mean maximum plasma concentration attained (C(max)), the mean time at which C(max) was attained, the elimination half-life (t(1/2)) and the total area under the plasma concentration vs. time curve (AUC) of quinine and its metabolites between the pregnant in non-pregnant women. There was no significant difference in quinine metabolism between pregnant and non-pregnant women and there is no need to adjust quinine dose when treating pregnant women.

Early treatment failure in severe malaria resulting from abnormally low plasma quinine concentrations

A patient admitted with severe Plasmodium falciparum malaria in western Thailand had an early treatment failure with quinine, despite full dosing. Plasma quinine concentrations were subtherapeutic. Abnormal quinine pharmacokinetics may explain sporadic reports of quinine treatment failures in severe malaria.

Quinine Pharmacokinetics and Pharmacodynamics in Children with Malaria Caused by Plasmodium falciparum

The aim of the present study was to assess the pharmacokinetics and the efficacy of a shorter than usual 5-day quinine treatment given orally to children in Cameroon with malaria caused by Plasmodium falciparum. Quinine (8.3 mg of base per kg of body weight every 8 h) was administered as a 2% formiate salt syrup for 5 days to 30 children (age range, 0.55 to 6.7 years) with uncomplicated falciparum malaria (initial parasitemia, 1.4 x 10(3) to 1.8 x 10(5)/microl). Quinine concentrations in plasma samples (five to nine per patient) were measured by liquid chromatography on days 1 to 3. Parasitemia was counted on days 0, 1, 2, 3, 4, 7, and 14. Pharmacokinetic and pharmacodynamic data were analyzed by population approaches by using NONMEM and WinBugs, respectively. The kinetics of quinine were best described by a one-compartment model with time-varying protein binding. Clearance and the volume of distribution were positively correlated with body weight and increased over time. Parasitemia was undetectable from day 3 to 14 in all children. The time to a 4-log reduction of the initial level of parasitemia (Ter) was related to the average quinine concentration from 0 to 72 h (Cav) as Ter = Tmin [1 + (C50/Cav)s], where sigmoidicity (s) is equal to 2, Tmin is the time to eradication at infinite Cav, and C50 is the value of Cav for which Ter is twice Tmin. The C50 distribution was unimodal, and all C50 values were less than 8 mg/liter, while Cav ranged from 5.9 to 18.3 mg/liter. The median (10th to 90th percentile) Ter was 47 h (range, 39 to 76 h). The efficacy of a 5-day treatment course should be evaluated in a larger clinical trial.

The influence of bile salts and mixed micelles on the pharmacokinetics of quinine in rabbits

The bioavailability of orally administered drugs can be influenced by interactions with food components and by physico-chemical conditions in the upper gastrointestinal tract. Normally, bile salts enhance the transport of lipophilic drugs across mucosal membranes. Bile salts are able to form stable mixed micelles consisting of fatty acids and phospholipids. Conventional micellar systems are known to solubilize lipophilic drugs having a low bioavailability. The influence of bile salts and mixed micelles on the pharmacokinetics of the lipophilic drug quinine was investigated in rabbits. Female rabbits were given intraduadenally quinine (5 mg/kg body weight) without and with incorporation into the micellar or mixed micellar systems. Blood was collected every 30 min for 6 h. In plasma, concentration of quinine was measured using HPLC. The plasma concentration–time profiles of quinine were significantly lower within the first 2 h after administration in presence of both the sodium salt of glycodeoxycholic acid (above the critical micellar concentration) as well as of mixed micellar systems consisting of glycodeoxycholic acid and palmitic acid and/or lecithin. The pharmacokinetic parameters AUC (relative bioavailability) and c max of quinine were significantly decreased by micellar systems in rabbits. These mixed micellar systems lower and not as expected, increase the absorption of quinine in vivo. Therefore, quinine should be orally administered at least 1 h before food intake, particularly before fat intake.

Quinine pharmacokinetics in chronic haemodialysis patients.

Quinine is often used to prevent muscle cramps in patients with chronic renal failure. A standard dose of 300 mg at bedtime is usually recommended, but little is known about the pharmacokinetics of quinine in the presence of renal failure. We studied the pharmacokinetics of quinine in eight normal subjects and eight patients with chronic renal failure on haemodialysis after a single oral dose of quinine sulphate (300 mg). The concentration of alpha1-acid glycoprotein (AAG), the major binding protein for quinine, was increased in haemodialysis patients compared with control subjects (1.52 g l-1 vs 0.63 g l-1 [mean difference 1.033; 95% CI 0.735, 1.330]) whereas albumin levels were decreased (30 g l-1 vs 40 g l-1 [mean difference 9.5; 95% CI 3.048, 15.952]). Accordingly, the free fraction of quinine was decreased (0.024 vs 0.063 [mean difference 0.0380; 95% CI 0.0221, 0.0539]) and the apparent volume of distribution tended to decrease (0.95 l kg-1 vs 1.43 l kg-1 [mean difference 0.480; 95% CI 0.193, 1.154]). The quinine binding ratio correlated with the plasma concentration of AAG but not that of albumin. The clearance of free (unbound) quinine was increased in haemodialysis patients compared with controls (67.9 ml min-1 kg-1 vs 41.1 ml min-1 kg-1 [mean difference -26.8; 95% CI, -56.994, 3.469]), and the area under the curve (AUC) of the two main metabolites, 3-hydroxyquinine and 10,11-dihydroxydihydroquinine were increased. In patients with chronic renal failure, there is an increase in plasma protein binding and in the clearance of free drug, resulting in lower plasma concentration of free quinine.

Interaction Trial between Artemether‐Lumefantrine (Riamet®) and Quinine in Healthy Subjects

Forty‐two healthy Caucasian subjects were randomized in a double‐blind, parallel three‐group study (14 subjects per group) to investigate potential electrocardiographic and pharmacokinetic interactions between the antimalarials artemether‐lumefantrine (six‐dose regimen of Riamet® over3 days) and quinine (2‐h intravenous infusion of 10 mg/kg body weight, not exceeding 600 mg in total, 2 h after the last dose of Riamet®). The study medications were all safe and well tolerated after all treatments. Neither the pharmacokinetics of lumefantrine nor the pharmacokinetics of quinine was influenced by the presence of the other drug. Plasma levels of artemether and dihydroartemisinin appeared to be lower following the combined treatment Riamet® + quinine, but this was not considered to be clinically relevant. Riamet® alone had no effect on QTc interval. Infusion of quinine alone caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine, with this effect being slightly but significantly greater when quinine was infused after Riamet®. It would thus appear that the inherent risk of QTc prolongation of IV quinine was enhanced by prior administration of Riamet®. However, these occasional QTc prolongations, which were small in magnitude and not correlated with plasma concentrations of any of the compounds, were not considered to be of clinical importance. In conclusion, overlapping therapy with artemether‐lumefantrine and IV quinine in the treatment of patients with complicated or multidrug‐resistant Plasmodium falciparum malaria may result in a modest increased risk of QTc prolongation, but this is far outweighed by the potential therapeutic benefit.

Effect of the grapefruit flavonoid naringin on pharmacokinetics of quinine in rats.

The effect of the grapefruit flavonoid naringin, an inhibitor of CYP3A4, on the pharmacokinetics of quinine in rats after oral or intravenous (i.v.) dosing of quinine was investigated. Female Wistar rats (wt 190-220 g) were used in two separate studies, i.e. oral and i.v. administration of quinine. The animals were divided into two groups, one served as control and the other group was pretreated with 25 mg/kg naringin once a day for 7 consecutive days before the pharmacokinetic study. On the study day, quinine (25 mg/kg) was administered to the rats by either the oral or i.v. route. Blood samples were collected at different times, up to 6 h after quinine administration. Plasma quinine concentration was assayed by HPLC. Pretreatment with naringin did not cause any significant change in the pharmacokinetics of quinine after the i.v. dose. However pretreatment with naringin led to a 208% increase in peak plasma concentration (Cmax), a 93% increase in time to reach Cmax (tmax), and a 152% increase in the area under the plasma concentration-time curve (AUC) of quinine after oral administration. Consequently, the oral bioavailability of quinine was significantly increased (p < 0.05) from 17% (control) to 42% after pretreatment with naringin. There was no significant difference in the elimination half-life (t(1/2)beta) of quinine between the two groups. These results suggest that pretreatment with the grapefruit flavonoid naringin is associated with increased oral bioavailability of quinine in rats.

Pharmacokinetics of quinine in obesity

Obesity can modify the pharmacokinetics of lipophilic drugs. As quinine is a lipophilic drug, this study was conducted to determine whether the pharmacokinetics of quinine is altered in obese subjects. Nine obese Thai men were compared with 8 age-matched lean men. After an oral dose of quinine had been given to the men, plasma quinine concentrations were measured up to 48 h after the dosing. Mean peak plasma quinine concentration in the obese group was significantly lower than that observed in the controls (4·0 ± 0·8 vs 5·0 ± 0·3 mg/L, P < 0·01). There were no significant differences in time to reach the peak plasma concentration, half-life and total clearance of quinine between the 2 groups. The mean clearances of quinine normalized to the ideal bodyweight (IBW) in the obese and the control groups were not significantly different (0·091 ± 0·018 vs 0·091 ± 0·024 L/h/kg IBW, P > 0·05). As there are similarities in the total clearance and the clearance of quinine based on IBW, the maintenance dose of quinine should be given to obese patients on the basis of ideal bodyweight, not on total bodyweight.

Grapefruit juice has no significant effect on the pharmacokinetics of quinine,

Grapefruit juice has no significant effect on the pharmacokinetics of quinine,