Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border

Hoglund, Richard M; Moussavi, Younis; Ruengweerayut, Ronnatrai; Cheomung, Anurak; Äbelö, Angela; Na‐Bangchang, Kesara

doi:10.1186/s12936-016-1181-1

Cited by 23 publications

(42 citation statements)

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“…With regard to the influence of race, the pharmacokinetic properties of chloroquine do not differ in African subjects as compared to Caucasians [64]. However, in a population of Thai individuals, a two-fold lower clearance was observed [10] for which no real explanations could be found (see ESM). In the published model, also volume of distribution deviated from what was found in other publications.…”

Section: Special Patient Populationsmentioning

confidence: 93%

“…After absorption, chloroquine extensively distributes across all tissues resulting in a very large volume of distribution of 200 L/kg which, combined with a slow elimination, results in a terminal half-life reported to vary between days and weeks depending on the sampling time used in the study [7,10,11]. The apparent half-life, however, is much shorter at 1.6 days [12].…”

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

“…Figure 1 shows concentration-time profiles that can be expected in a standard individual of 70 kg with this high loading dose over 48 h according to Pussard et al [47] (panel B) compared to one of the currently proposed dosages for COVID-19-associated pneumonia (panel A), which is a fixed dose of 3300 mg over 5 days with 600 mg and 300 mg on the first day (see ESM for details). To generate these plots, the pharmacokinetic model published by Zhao et al [20] was used after it had been extensively evaluated for its predictive performance with observations from a large number of other pharmacokinetic studies including studies in children (from 0.5 to 18 years of age) and adults with renal dysfunction [10,18,19,[47][48][49][50][51][52] (see ESM for details about the model and simulations). In this figure, it can be seen that the high loading dose schedule of Pussard et al [47] may lead to higher chloroquine plasma concentrations at the beginning of therapy without increasing the maximum concentration compared to the standard dose for individuals of 70 kg without renal dysfunction.…”

Section: What Can We Learn From Chloroquine Studies Performed In Adulmentioning

confidence: 99%

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Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties

et al. 2020

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Since in vitro studies and a preliminary clinical report suggested the efficacy of chloroquine for COVID-19-associated pneumonia, there is increasing interest in this old antimalarial drug. In this article, we discuss the pharmacokinetics and safety of chloroquine that should be considered in light of use in SARS-CoV-2 infections. Chloroquine is well absorbed and distributes extensively resulting in a large volume of distribution with an apparent and terminal half-life of 1.6 days and 2 weeks, respectively. Chloroquine is metabolized by cytochrome P450 and renal clearance is responsible for one third of total clearance. The lack of reliable information on target concentrations or doses for COVID-19 implies that for both adults and children, doses that proved effective and safe in malaria should be considered, such as 'loading doses' in adults (30 mg/kg over 48 h) and children (70 mg/kg over 5 days), which reported good tolerability. Here, plasma concentrations were < 2.5 μmol/L, which is associated with (minor) toxicity. While the influence of renal dysfunction, critical illness, or obesity seems small, in critically ill patients, reduced absorption may be anticipated. Clinical experience has shown that chloroquine has a narrow safety margin, as three times the adult therapeutic dosage for malaria can be lethal when given as a single dose. Although infrequent, poisoning in children is extremely dangerous where one to two tablets can potentially be fatal. In conclusion, the pharmacokinetic and safety properties of chloroquine suggest that chloroquine can be used safely for an acute virus infection, under corrected QT monitoring, but also that the safety margin is small, particularly in children.

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Section: Special Patient Populationsmentioning

confidence: 93%

Section: General Pharmacokinetic Propertiesmentioning

confidence: 99%

Section: What Can We Learn From Chloroquine Studies Performed In Adulmentioning

confidence: 99%

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Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties

et al. 2020

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“…Each whole blood concentration-time curve was summarised by its peak concentration, denoted C max . The pharmacokinetic model estimated from whole blood concentrations [13] predicted a wider range of values for C max than the plasma based model (supplementary Figure S3 shows the predicted distributions for a 70 kg adult). Assuming a plasma to whole blood concentration ratio of 3, the whole blood based model also predicted higher median concentrations for all regimens.…”

Section: Resultsmentioning

confidence: 99%

“…This specifically adjusted for the presence of the desethyl metabolite and for the non-observed peak concentrations in 200 (78%) of the patients. The whole blood chloroquine concentration associated with 1% mortality was 13µmol/L (95% CI, [10][11][12][13][14][15][16]. This is considered to be the lowest mortality for which a reliable estimate can be derived from the data.…”

Section: Resultsmentioning

confidence: 99%

Concentration-dependent mortality of chloroquine in overdose

Watson

Tärning

Hoglund

et al. 2020

Preprint

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Background: Hydroxychloroquine and chloroquine have been used extensively in malaria and rheumatological conditions. Although generally safe and well tolerated they are potentially lethal in overdose. These two drugs are now candidates for the prevention and treatment of COVID19. In vitro data suggest that high concentrations and thus high doses will be needed if they are to be of benefit, but as yet there is no convincing evidence they are clinically effective. Nevertheless they are already being used very widely and fatal accidental overdoses have been reported.Methods: Individual data from prospectively studied French patients who had taken intentional chloroquine overdoses and were managed in the national toxicology intensive care unit in Paris were pooled. Bayesian logistic regression was used to estimate a concentration-fatality curve. The probabilities of fatal iatrogenic toxicity with the chloroquine regimens currently being trialled for the treatment of COVID19 were estimated from a combined pharmacokineticpharmacodynamic model.Findings: In total, 258 patients were studied of whom 26 died (10%). There was a steep sigmoid relationship between admission whole blood chloroquine concentrations and death. Concentrations above 13µmol/L (95% credible interval (C.I.), 10 to 16) were associated with greater than 1% mortality. Based on peak concentrations, absolute fatality ratios in the high dose arm (chloroquine base equivalent adult dose of 600mg given twice daily for ten days) of a recently terminated trial were estimated between 0.06% (90kg adult, 95%C.I. 0 to 0.3%) and 4.8% (40kg adult, 95% C.I. 1.9 to 9.7%). This regimen results in peak concentrations above 10µmol/L in more than 60% of adults weighing 70kg. The other high dose regimens trialled currently for COVID19 result in peak concentrations above 10µmol/L in only 0.2% of adults weighting 70kg.Interpretation: High-dose chloroquine treatment regimens which result in whole blood chloroquine concentrations below 10µmol/L for the majority of patients should not result in life-threatening cardiovascular toxicity. Evidence before this studyWe searched Pubmed using the terms (chloroquine OR hydroxychloroquine) AND (suicide OR intoxication OR poisoning) AND concentration NOT mice, which returned 90 results. After excluding reviews, case reports with concentrations measured post mortem, healthy volunteer studies, animal studies and laboratory studies, 16 publications were retained. Of these, 12 were case reports and 4 were hospital cohorts. Case reports exhibited significant bias towards individuals with high concentrations who survived. Of the 4 hospital cohorts, we extracted data manually from one, and obtained the original data for two.Added value of this study We provide an objective methodology to evaluate the risk of overdose for chloroquine treatment or prevention regimens currently being trialled in COVID19. This can be used to assess formally the risk-benefit trade-off when administering large doses for treatment .Implications of all the available evide...

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Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study

Abd-Rahman

Marquart

Gobeau

et al. 2020

Clin Pharma and Therapeutics

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Chloroquine has been used for the treatment of malaria for > 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PK/PD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study. We analyzed data from 24 healthy subjects who were inoculated with bloodstage P. vivax malaria and administered a standard treatment course of chloroquine. The PK of chloroquine and desethylchloroquine was described by a two-compartment model with first-order absorption and elimination. The relationship between plasma and whole blood concentrations of chloroquine and P. vivax parasitemia was characterized by a PK/PD delayed response model, where the equilibration half-lives were 32.7 hours (95% confidence interval (CI) 27.4-40.5) for plasma data and 24.1 hours (95% CI 19.0-32.7) for whole blood data. The estimated parasite multiplication rate was 17 folds per 48 hours (95% CI 14-20) and maximum parasite killing rate by chloroquine was 0.213 hour −1 (95% CI 0.196-0.230), translating to a parasite clearance half-life of 4.5 hours (95% CI 4.1-5.0) and a parasite reduction ratio of 400 every 48 hours (95% CI 320-500). This is the first study that characterized the PK/PD relationship between chloroquine plasma and whole blood concentrations and P. vivax clearance using a semimechanistic population PK/PD modeling. This PK/PD model can be used to optimize dosing scenarios and to identify optimal dosing regimens for chloroquine where resistance to chloroquine is increasing. Globally, 225 million cases of malaria have been reported with 7.5 million cases due to Plasmodium vivax. 1 Malaria causes an estimated 405,000 deaths worldwide in which 67% involve children aged under 5 years. 1 Chloroquine was the cornerstone of malaria treatment but the spread of drug resistance has rendered chloroquine ineffective for the treatment of P. falciparum malaria in almost all

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Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border

Cited by 23 publications

References 45 publications

Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties

Chloroquine for SARS-CoV-2: Implications of Its Unique Pharmacokinetic and Safety Properties

Concentration-dependent mortality of chloroquine in overdose

Population Pharmacokinetics and Pharmacodynamics of Chloroquine in a Plasmodium vivax Volunteer Infection Study

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