scholarly journals Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan

2021 ◽  
Vol 12 ◽  
Author(s):  
Muhammad Muaaz Munir ◽  
Huma Rasheed ◽  
Muhammad Imran Khokhar ◽  
Rizwan Rasul Khan ◽  
Hafiz Asad Saeed ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Concentration ◽  
Goodness Of Fit ◽  
Volume Of Distribution ◽  
Surgical Patients ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Concentration Data ◽  
Population Pharmacokinetic Modeling

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan.Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration–time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks.Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively.Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

scholarly journals Population Pharmacokinetic Analysis of Voriconazole Plasma Concentration Data from Pediatric Studies

2008 ◽  
Vol 53 (3) ◽  
pp. 935-944 ◽  
Author(s):  
Mats O. Karlsson ◽  
Irja Lutsar ◽  
Peter A. Milligan
Keyword(s):  
Body Weight ◽  
Plasma Concentration ◽  
Patient Population ◽  
Pediatric Patients ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Concentration Data ◽  
Mixed Effect

ABSTRACT Voriconazole is a potent triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present population pharmacokinetic analysis evaluated voriconazole plasma concentration-time data from three studies of pediatric patients of 2 to <12 years of age, incorporating a range of single or multiple intravenous (i.v.) and/or oral (p.o.) doses. An appropriate pharmacokinetic model for this patient population was created using the nonlinear mixed-effect modeling approach. The final model described voriconazole elimination by a Michaelis-Menten process and distribution by a two-compartment model. It also incorporated a statistically significant (P < 0.001) influence of the CYP2C19 genotype and of the alanine aminotransferase level on clearance. The model was used in a number of deterministic simulations (based on various fixed, mg/kg of body weight, and individually adjusted doses) aimed at finding suitable i.v. and p.o. voriconazole dosing regimens for pediatric patients. As a result, 7 mg/kg twice a day (BID) i.v. or 200 mg BID p.o., irrespective of body weight, was recommended for this patient population. At these doses, the pediatric area-under-the-curve (AUC) distribution exhibited the least overall difference from the adult AUC distribution (at dose levels used in clinical practice). Loading doses or individual dosage adjustments according to baseline covariates are not considered necessary in administering voriconazole to children.

scholarly journals Population Pharmacokinetics of Tenofovir in Pregnant and Postpartum Women using Tenofovir Disoproxil Fumarate.

2020 ◽  
pp. AAC.02168-20
Author(s):  
Ahizechukwu C. Eke ◽  
Kensuke Shoji ◽  
Brookie M. Best ◽  
Jeremiah D. Momper ◽  
Alice M. Stek ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Tenofovir Disoproxil Fumarate ◽  
Post Partum ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Postpartum Women ◽  
Concentration Data ◽  
Mixed Effects Modeling

Pharmacokinetics of drugs can be affected by physiologic changes during pregnancy. Our aim was to assess the influence of covariates on tenofovir (TFV) pharmacokinetics in pregnant and postpartum women receiving tenofovir disoproxil fumarate (TDF). Population pharmacokinetic parameters estimates and the influence of covariates were assessed using nonlinear mixed effects modeling (NONMEM 7.4). Forty-six women had intensive pharmacokinetic evaluations during the second and third trimesters of pregnancy, and repeated post-partum. A two-compartment pharmacokinetic model with allometric scaling for body weight and first-order absorption best described the tenofovir plasma concentration data. Apparent oral clearance (CL/F) and volume of distribution (Vss/F) were increased during pregnancy. Weight, serum creatinine (SCr), pregnancy, albumin and age were associated with TFV CL/F during univariate assessment, but in the multivariate analysis, changes in CL/F and Vss/F were only associated with increased body weight and enhanced renal function. Due to greater weight and lower SCr during pregnancy, CL/F was 28% higher during pregnancy compared to postpartum. In the final model CL/F (L/h) was described as 2.07*(SCr/0.6)0.65*Weight0.75, with a low between subject variability (BSV) of 24%. The probability of target attainment (proportion exceeding AUC>1.99 mcg*h/mL, the 10th percentile of average TDF exposure for non-pregnant historical controls) was 68%, 80%, 87%, and 93% above target with 300mg, 350mg, 400mg and 450mg of TDF respectively during pregnancy, and 88%, 92%, 96% and 98% above target with same doses in postpartum women. Dose adjustment of TDF during pregnancy is not generally warranted but any modification should be based on weight and renal function.

scholarly journals Population Pharmacokinetic Study of Prophylactic Fluconazole in Preterm Infants for Prevention of Invasive Candidiasis

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Yu Kyong Kim ◽  
Juyoung Lee ◽  
Jaeseong Oh ◽  
Su-jin Rhee ◽  
Seung Han Shin ◽  
...  
Keyword(s):  
Body Weight ◽  
Preterm Infants ◽  
Goodness Of Fit ◽  
Pharmacokinetic Model ◽  
Dose Interval ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Oral Fluconazole ◽  
Systemic Fungal Infection ◽  
Population Pharmacokinetic Study

ABSTRACT Fluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen. A pharmacokinetic model was developed using 301 fluconazole concentrations from 75 preterm infants with a baseline body weight (WT) ranging from 0.5 to 1.5 kg and an estimated glomerular filtration rate (eGFR) ranging from 12.9 to 58.5 ml/min/1.73 m2. Eligible infants received an intravenous or oral dose of 3 mg/kg of body weight of fluconazole, twice weekly with a ≥72-h dose interval, for 4 weeks. The model was qualified with basic goodness-of-fit diagnostics, visual predictive checks, and bootstrapping. The fluconazole pharmacokinetics was well described with a one-compartment linear model with a proportional residual error. The population clearance (CL) and volume of distribution (V) were derived as 0.0197 × (WT/1.00)0.746 × (eGFR/25.0)0.463 × exp(η) and 1.04 × WT × exp(η), respectively. Such covariate analyses augment the awareness of the need for personalized dosing in preterm infants. (This study has been registered at ClinicalTrials.gov under identifier NCT01683760.)

Population Pharmacokinetics of Siplizumab (MEDI-507), a Humanized Anti-CD2 Monoclonal Antibody, in Cancer Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2670-2670
Author(s):  
Chunlin Chen ◽  
John E Janik ◽  
Karen Kaucic ◽  
Lorin Roskos ◽  
Bahija Jallal ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Body Weight ◽  
Serum Concentration ◽  
Dose Escalation ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Serum Concentrations ◽  
Concentration Data ◽  
Non Linear ◽  
Volumes Of Distribution

Abstract Abstract 2670 Poster Board II-646 Introduction: Siplizumab, a humanized IgG1k class monoclonal antibody that targets CD2 expressing T-and NK-cells, was evaluated in phase I dose-escalation trials in patients with CD2-positive lymphoproliferative disorder. The objective of this study was to develop a population pharmacokinetic (PK) model for siplizumab and identify covariates that could explain the variability in siplizumab pharmacokinetic parameters. Methods: A Phase 1, open label, dose-escalation study was conducted in 29 patients (14 males/15 females, age range 34–79 years) who received 0.2–4.8 mg/kg of siplizumab as 1-3 consecutive daily doses every 14 days for a total of 1-8 cycles. Siplizumab serum concentration data was analyzed using a nonlinear mixed effects modeling approach with software (NONMEM). Based on exploratory analysis, 1-and 2-compartment non-linear models were evaluated. Demographic covariates including body weight, age, sex and race (Caucasian/Black/Asian) were screened using Generalized Additive Model (GAM) analysis. Covariates selected during the GAM analysis were further tested for significance in NONMEM using the forward inclusion and backward elimination approach. Results: Siplizumab concentrations were obtained from all 29 patients in the study yielding a total of 619 serum concentration observations. Pronounced non-linearity in siplizumab serum concentrations was observed after the initial and later dosing cycles, with serum concentrations declining faster at lower dose levels. The data was best described by a two-compartment pharmacokinetic model with zero-order input with parallel linear and non-linear elimination pathways. Goodness of fit plots and model diagnostics indicated good agreement between observed and model predicted serum concentration values. The population estimates for linear clearance was 0.168 L/day with inter-subject variability (ISV) of 50%, and inter-compartmental clearance was 2.83 L/day. Nonlinear elimination parameters, Vmax and Km were 10.32 mcg/day (56% ISV) and 51.8 mcg/L, respectively. Sex of the patients was identified as a significant covariate impacting volumes of distribution. Male patients had higher central and peripheral volumes of distribution of 2.8 L and 3.0 L, respectively, compared to1.38 L and 2.4 L in females [32% vs 50% ISV]. Conclusion: The serum concentration-time profile of siplizumab was adequately described by a two-compartment non-linear PK model. Population parameters were precisely estimated and correspond well to reported PK behaviour of monocolonal antibodies with significant target mediated elimination. The lower volume distribution in females is most likely due to lower body weight compared to males in this study. The population PK model combined with pharmacodynamic data could serve as a tool to guide selection of optimal dose regimens for siplizumab. Disclosures: No relevant conflicts of interest to declare.

ORGAN FAILURE AND C-REACTIVE PROTEIN BOTH AFFECT MIDAZOLAM CLEARANCE IN CRITICALLY ILL CHILDREN: A POPULATION PK MODEL

2015 ◽  
Vol 101 (1) ◽  
pp. e1.8-e1
Author(s):  
Nienke J Vet ◽  
Janneke M Brussee ◽  
Matthijs de Hoog ◽  
Miriam G Mooij ◽  
Carin WM Verlaat ◽  
...  
Keyword(s):  
Body Weight ◽  
Organ Failure ◽  
Critically Ill ◽  
Volume Of Distribution ◽  
Critically Ill Children ◽  
Population Pharmacokinetic ◽  
C Reactive Protein ◽  
Population Pharmacokinetic Modeling ◽  
Reactive Protein ◽  
Organ Failures

ObjectivesTo study the effect of organ failure and inflammation on midazolam clearance in critically ill children, using population pharmacokinetic modeling.MethodsA total of 83 critically ill children (median age 5 months (range 1 day-17 years), n=523 samples) receiving intravenous midazolam for continuous sedation during mechanical ventilation were included. Disease severity was described using the validated and clinically used scores PELOD, PIM2 and PRISM II. Cytokines (IL-1, IL-2, IL-6, TNF-a) and C-reactive protein (CRP) were used as markers for inflammation. A population pharmacokinetic model for midazolam was developed using NONMEM 7.3. Body weight, age, severity of organ failure and inflammatory markers were considered as potential covariates.ResultsIn a two-compartmental PK model, body weight was found as most significant covariate for clearance and volume of distribution. Moreover, both severity of organ failure (PELOD) and inflammation (IL6 and CRP) were significant determinants of clearance (p<0.01), and either of these factors improved the model significantly. With increasing number of organ failures, midazolam clearance significantly reduced. CRP was linearly correlated with clearance (slope −0.095), with higher CRP levels resulting in lower clearances. Either one of the covariates could explain part of the variability in clearance.ConclusionFor midazolam clearance, apart from body weight, we found organ failure reflected by the PELOD score, and inflammation reflected by IL6 and CRP, as significant covariates. Most likely this effect is due to reduced activity of CYP3A in critically ill mechanically ventilated children. Both CRP concentration and organ failure should be considered when dosing midazolam and potentially other CYP3A substrates in critically ill children.

scholarly journals Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients

2015 ◽  
Vol 59 (11) ◽  
pp. 6755-6762 ◽  
Author(s):  
Yumiko Matsuo ◽  
Toru Ishibashi ◽  
Alan S. Hollister ◽  
Toshihiro Wajima
Keyword(s):  
Renal Function ◽  
Plasma Concentration ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
The United States ◽  
Volume Of Distribution ◽  
Elderly Subjects ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Concentration Data

ABSTRACTPeramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

scholarly journals Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults

2018 ◽  
Vol 62 (7) ◽  
Author(s):  
Roeland E. Wasmann ◽  
Rob ter Heine ◽  
Eric P. van Dongen ◽  
David M. Burger ◽  
Vincent J. Lempers ◽  
...  
Keyword(s):  
Reference Value ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Normal Weight ◽  
Pharmacokinetic Parameters ◽  
Morbidly Obese ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Obese Subjects

ABSTRACT In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have been shown to influence the pharmacokinetics of drugs. Anidulafungin is frequently used in critically ill patients, and to achieve optimal efficacy, it is essential that its dose is appropriate for each patient's characteristics. We combined data from obese subjects with data from normal-weight subjects and determined an optimal dosing regimen for obese patients by population pharmacokinetic modeling. Twenty adults, 12 of which were normal-weight healthy subjects (median weight, 67.7 kg; range, 61.5 to 93.6 kg) and 8 of which were morbidly obese subjects (median weight, 149.7 kg; range, 124.1 to 166.5 kg) were included in the analysis. Subjects received a single dose of 100 mg anidulafungin intravenously over 90 min, upon which blood samples were obtained. Monte Carlo simulations were performed to optimize dosing in obesity. A three-compartment model and equal volumes of distribution described the data best. Total body weight was identified as a descriptor for both clearance and the volume of distribution, but the effect of weight on these parameters was limited. Simulations showed that with the licensed 100-mg dose, more than 97% of subjects with a weight above 140 kg will have an area under the concentration-time curve from 0 to 24 h of less than 99 mg · h/liter (the reference value for normal-weight individuals). We found that in obese and normal-weight subjects, weight influenced both of the anidulafungin pharmacokinetic parameters clearance and volume of distribution, implying a lower exposure to anidulafungin in (morbidly) obese individuals. Consequently, a 25% increase in the loading and maintenance doses could be considered in patients weighing more than 140 kg.

Population Pharmacokinetics of Enoxaparin in Children at Risk for Symptomatic Thromboembolism.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1071-1071
Author(s):  
Mirjam Nadine Trame ◽  
Lesley Mitchell ◽  
Christoph Male ◽  
Jeffrey S. Barrett ◽  
Georg Hempel ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Maintenance Dose ◽  
Factor Xa ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Safety And Efficacy ◽  
Off Label ◽  
Final Population

Abstract Abstract 1071 Poster Board I-93 Introduction: Enoxaparin, a low-molecular-weight-heparin (LMWH), is used off-label in children to prevent symptomatic thromboembolism when acute anticoagulation or secondary prevention is required due to venous thrombosis or stroke. This investigation was conducted because of concerns of altered pharmacokinetics and a lack of safety and efficacy data when used in children. Patients and Methods: Data of 126 children and adolescents with a median age of 5.9 years receiving enoxaparin either as a once or twice daily dosing regimen were analyzed. Children < 12 months of age received a starting dose of 1.5 mg/kg followed by a maintenance dose of 1.3 mg/kg. Children > 12 months of age were started on 1 mg/kg followed by a maintenance dose of 1 mg/kg. Blood samples were drawn after patients reached steady-state on their maintenance dose at baseline prior to the next dose, and at 2, 4, 8 and 12 hours after administration. The median enoxaparin concentration in our population resulted in a median anti-factor Xa activity of 0.4 U/ml (range 0 – 1 U/ml anti-factor Xa). By means of population pharmacokinetics using nonlinear mixed-effects modelling (NONMEM) plasma concentration-time data were analyzed. Several covariates such as age, body weight and body surface area were tested on their effects on the pharmacokinetic parameters. Results: Using a two-compartment model the enoxaparin kinetics were described sufficiently. By using body weight and age as covariates for clearance (CL) and central volume of distribution (V1) the best results were obtained. The final population estimates of enoxaparin resulted to be: CL 7.11 ml h-1 kg-1 ± 14.3%, V1 7.31 ml kg-1 ± 33.5%, intercompartimental clearance (Q) 194 ml h-1 ± 24.7%, peripheral volume of distribution (V2) 45.1 l ± 52.5% and absorption rate (ka) 0.0799 h-1 ± 21.7% (estimates ± standard errors). Interindividual variability (IIV) was found to be 75.6% for CL and 78.4% for Q, respectively. Figure 1 shows the predicted activity time-course versus the measured activities for a representative patient. The model is capable of describing all aging and dosing groups of our childhood population (neonates, infants to adolescents). Conclusion: The high IIV in CL and Q in our population underlines the need for monitoring the activity and individualizing the dose. Further population pharmacokinetic/-dynamic investigations should be conducted to predict target enoxaparin levels or other new antithrombotic drugs for more safety and efficacy during antithrombotic therapy when used in children. Disclosures: Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism..

scholarly journals Population Pharmacokinetic Study of Amikacin Administered Once or Twice Daily to Febrile, Severely Neutropenic Adults

1998 ◽  
Vol 42 (4) ◽  
pp. 849-856 ◽  
Author(s):  
Michel Tod ◽  
Olivier Lortholary ◽  
Delphine Seytre ◽  
Rémi Semaoun ◽  
Bernard Uzzan ◽  
...  
Keyword(s):  
Body Weight ◽  
Creatinine Clearance ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Dosing Regimen ◽  
Mixed Effect ◽  
Neutropenic Patients ◽  
Kinetics Of

ABSTRACT Once-daily (o.d.) administration of 20 mg of amikacin per kg of body weight to neutropenic patients has been validated by clinical studies, but amikacin pharmacokinetics have been documented only for the 7.5-mg/kg twice-daily (b.i.d.) regimen in this population. In order to determine in neutropenic patients (i) the influence of the dosing regimen on the kinetics of amikacin, (ii) the linearity of kinetics of amikacin in the range of 7.5 to 20 mg/kg, and (iii) the influence of patient characteristics on the disposition of amikacin and (iv) to provide a rationale for dosing recommendations, we evaluated the population pharmacokinetics of amikacin administered to 57 febrile neutropenic adults (neutrophil count, <500/mm3) being treated for a hematological disorder and receiving amikacin at 7.5 mg/kg b.i.d. (n = 29) or 20 mg/kg o.d. (n = 28) and administered intravenously over 0.5 h. A total of 278 blood samples were obtained (1 to 14 samples per patient) during one or several administration intervals (1 to 47). Serum amikacin levels were measured by the enzyme-multiplied immunoassay technique. A mixed-effect modeling approach was used to fit a bicompartmental model to the data (NONMEM software). The influences of the dosing regimen and the demographic and biological indices on the pharmacokinetic parameters of amikacin were evaluated by the maximum-likelihood ratio test on the population model. The dosing regimen had no influence on amikacin pharmacokinetic parameters, i.e., the kinetics of amikacin were linear over the range of 7.5 to 20 mg/kg. Amikacin elimination clearance (CL) was only correlated with creatinine clearance or its covariates, namely, sex, age, body weight, and serum creatinine level. The interindividual variability of CL was 21%, while those of the central volume of distribution, the distribution clearance, and the tissue volume of distribution were 15, 30, and 25%, respectively. On the basis of the expected distribution of amikacin concentrations in this population, dosing recommendations as a function of creatinine clearance (CLCR) are proposed: for patients with normal renal function (CLCR of 80 to 130 ml/min), 20 mg/kg o.d. is recommended, whereas for patients with severe renal impairment (CLCR, 10 to 20 ml/min), a dosage of 17 mg/kg every 48 h is recommended.

scholarly journals Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

2001 ◽  
Vol 45 (6) ◽  
pp. 1803-1809 ◽  
Author(s):  
Sanjeev Krishna ◽  
Nelamangala V. Nagaraja ◽  
Tim Planche ◽  
Tsiri Agbenyega ◽  
George Bedo-Addo ◽  
...  
Keyword(s):  
Body Weight ◽  
Severe Malaria ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Intravenous Route ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Loading Dose

ABSTRACT 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 β phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized 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.

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