Pharmacokinetics of quinine in children

Shann, Frank; Stace, John; Edstein, Michael D.

doi:10.1016/s0022-3476(85)80692-2

Cited by 39 publications

(20 citation statements)

References 8 publications

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“…The two sites of quinine injection (10 mg/kg to each anterior thigh) were considered a single-depot compartment because the injections were administered almost simultaneously, and the bioavailability of intramuscular quinine was assumed to be complete (100%) (20). Demographic data and clinical admission and laboratory data were used as potential covariates to assess their relationship with derived population pharmacokinetic parameters for quinine.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

Krishna

Nagaraja

Planche

et al. 2001

Antimicrob Agents Chemother

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We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n ‫؍‬ 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] ‫؍‬ 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V 1 ] ‫؍‬ 0.65 liter/kg; volume of distribution at steady state ‫؍‬ 1.41 liter/kg; half-life at ␤ phase ‫؍‬ 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weightnormalized CL and V 1 . Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.Although quinine is one of the oldest drugs in the pharmacopoeia, the optimum usage of quinine in children with severe malaria is still debated (12, 29). The choice of route and dose of quinine for children with severe malaria will vary depending on circumstances and particularly on the capability of administering intravenous infusions reliably. Quinine is the drug of choice for the management of severe malaria in most areas of the world, and it is frequently deployed in conditions where intravenous infusions cannot be rapidly established or reliably monitored.Recent pharmacokinetic studies using African children have revived the intramuscular route as an alternative, cheaper, practicable, and potentially safer route for quinine administration (15, 25,27). However, classical pharmacokinetic studies are not always applicable to populations at highest risk of death from Plasmodium falciparum infection. One of the most important risk factors that identify these children is the complication of lactic acidosis (plasma or whole blood lactate concentration of Ն5 mmol/liter) (11). Dichloroacetate (DCA) is a potential treatment for malaria-associated lactic acidosis (7).We recently conducted a randomized, double-blind, placebo-controlled investigation to test the hypothesis that treatment with the lactate-lowering drug DCA, given with quinine, significantly improved morbidity and mortality in Ghanaian children with lactic acidosis due to severe P. falciparum malaria infection. This report describes the population pharmacokinetics of a loading dose of intramuscular quinine dihydrochloride (20 mg/kg of body weight) in 120 patients. The size of this study also allows assessment of covariables that may be important in influencing quinine kinetics. The ...

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Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

Krishna

Nagaraja

Planche

et al. 2001

Antimicrob Agents Chemother

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“…The early studies on quinine treatment for children with malaria were carried out in Asia, [65,104,1481 whereas more recent studies have established the pharmacokinetics of quinine in African children with moderate or severe malaria, Plasma concentration profiles following the intramuscular or intravenous route of administration are similar, although there is more variability in plasma concentrations following intramuscular injection. There is also some evidence that profiles after nasogastric administration are also similar to the those following the parenteral route.l 1041 In 5 studies which examined the pharmacokinetics of intravenous quinine in severe childhood malaria, and fitted plasma concentration profiles to I or 2 compartment models, the mean Vd ranged from 0.45 to 1.22 L/kg, tY2 Z from 10.7 to 16.4 hours and systemic clearances (CL) from 0.027 to 0.0816 L/h/kg.…”

Section: Childrenmentioning

confidence: 99%

Pharmacokinetics of Quinine, Chloroquine and Amodiaquine

Krishna

White

1996

Clinical Pharmacokinetics

273

189

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Malaria is associated with a reduction in the systemic clearance and apparent volume of distribution of the cinchona alkaloids; this reduction is proportional to the disease severity. There is increased plasma protein binding, predominantly to alpha 1-acid glycoprotein, and elimination half-lives (in healthy adults quinine t1/2z = 11 hours, quinidine t1/2z = 8 hours) are prolonged by 50%. Systemic clearance is predominantly by hepatic biotransformation to more polar metabolites (quinine 80%, quinidine 65%) and the remaining drug is eliminated unchanged by the kidney. Quinine is well absorbed by mouth or following intramuscular injection even in severe cases of malaria (estimated bioavailability more than 85%). Quinine and chloroquine may cause potentially lethal hypotension if given by intravenous injection. Chloroquine is extensively distributed with an enormous total apparent volume of distribution (Vd) more than 100 L/kg, and a terminal elimination half-life of 1 to 2 months. As a consequence, distribution rather than elimination processes determine the blood concentration profile of chloroquine in patients with acute malaria. Parenteral chloroquine should be given either by continuous intravenous infusion, or by frequent intramuscular or subcutaneous injections of relatively small doses. Oral bioavailability exceeds 75%. Amodiaquine is a pro-drug for the active antimalarial metabolite desethylamodiaquine. Its pharmacokinetic properties are similar to these of chloroquine although the Vd is smaller (17 to 34 L/kg) and the terminal elimination half-life is 1 to 3 weeks.

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“…These findings provide further evidence for a possible role of AGP in the binding of quinine in vivo. While changes in the degree of binding might be expected to influence both the therapeutic efficacy and toxicity of QN, studies of the pharmacokinetics of QN in children (Shann et al, 1985) suggest QN to be of low to intermediate clearance. Hence, free concentrations of QN may not increase in response to a change in the free fraction of QN.…”

Section: Relationship Between Agp Concentration and Qn Bindingmentioning

confidence: 99%

Effect of Plasmodium falciparum malaria infection on the plasma concentration of alpha 1‐acid glycoprotein and the binding of quinine in Malawian children.

Mansor

Molyneux

Taylor

et al. 1991

Brit J Clinical Pharma

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3 The mean unbound QN fraction was significantly less (P < 0.00001) in patients with malaria (0.128 ± 0.037) than in controls (0.193 ± 0.051) and significantly higher (P = 0.02) in convalescence (0.153 ± 0.067) than during acute illness. 4 There were highly significant negative correlations between plasma AGP concentration and the free QN fraction in spiked plasma samples (r = -0.534, P < 0.0001, n = 93) and in clinical samples (r = -0.484, P < 0.00001, n = 225). There was a significant positive correlation between plasma concentrations of AGP and another acute phase reactant, C reactive protein (P < 0.001).

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Pharmacokinetics of quinine in children

Cited by 39 publications

References 8 publications

Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

Pharmacokinetics of Quinine, Chloroquine and Amodiaquine

Effect of Plasmodium falciparum malaria infection on the plasma concentration of alpha 1‐acid glycoprotein and the binding of quinine in Malawian children.

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