Chloramphenicol Pharmacokinetics in African children with severe malaria

Article published in Journal of tropical pediatricsThe objective of this study was to determine if the current dosage regimen for chloramphenicol (CAP) administered to children with severe malaria (SM) for presumptive treatment of concomitant bacterial meningitis achieves steady state plasma CAP concentrations within the reported therapeutic range of 10–25 mg/l. Fifteen children (11 male, 4 female) with a median age of 45 months (range: 10–108 months) and having SM, were administered multiple intravenous doses (25 mg/kg, 6 hourly for 72 h) of chloramphenicol sodium succinate (CAPS) for presumptive treatment of concomitant bacterial meningitis. Blood samples were collected over 72 h, and plasma CAPS, CAP and CSF CAP concentrations determined by high performance liquid chromatography. Average steady state CAP concentrations were approximately 17 mg/l, while mean fraction unbound (0.49) and CSF/plasma concentration ratio (0.65) were comparable to previously reported values in Caucasian children. Clearance was variable (mean^4.3 l/h), and trough plasma concentrations during the first dosing interval were approximately 6 mg/l. Simulations indicated that an initial of loading dose of 40 mg/kg CAPS, followed by a maintenance dose of 25 mg/kg every 6 h would result in trough CAP concentrations of approximately 10 mg/l and peak concentrations _25 mg/l throughout the treatment period. The current dosage regimen for CAP needs to include a loading dose of 40 mg/kg CAPS to rapidly achieve plasma CAP concentrations within the reported therapeutic range.The objective of this study was to determine if the current dosage regimen for chloramphenicol (CAP) administered to children with severe malaria (SM) for presumptive treatment of concomitant bacterial meningitis achieves steady state plasma CAP concentrations within the reported therapeutic range of 10–25 mg/l. Fifteen children (11 male, 4 female) with a median age of 45 months (range: 10–108 months) and having SM, were administered multiple intravenous doses (25 mg/kg, 6 hourly for 72 h) of chloramphenicol sodium succinate (CAPS) for presumptive treatment of concomitant bacterial meningitis. Blood samples were collected over 72 h, and plasma CAPS, CAP and CSF CAP concentrations determined by high performance liquid chromatography. Average steady state CAP concentrations were approximately 17 mg/l, while mean fraction unbound (0.49) and CSF/plasma concentration ratio (0.65) were comparable to previously reported values in Caucasian children. Clearance was variable (mean=4.3 l/h), and trough plasma concentrations during the first dosing interval were approximately 6 mg/l. Simulations indicated that an initial of loading dose of 40 mg/kg CAPS, followed by a maintenance dose of 25 mg/kg every 6 h would result in trough CAP concentrations of approximately 10 mg/l and peak concentrations <25 mg/l throughout the treatment period. The current dosage regimen for CAP needs to include a loading dose of 40 mg/kg CAPS to rapidly achieve plasma CAP concentrations within the reported therapeutic range

Population pharmacokinetics of a single daily intramuscular dose of gentamicin in children with severe malnutrition

Article published in Journal of Antimicrobial ChemotherapyObjectives: The World Health Organization recommends that all children admitted with severe malnutrition should routinely receive parenteral ampicillin and gentamicin; despite this, mortality remains high. Since this population group is at risk of altered volume of distribution, we aimed to study the population pharmacokinetics of once daily gentamicin (7.5 mg/kg) in children with severe malnutrition and to evaluate clinical factors affecting pharmacokinetic parameters. Methods: Thirty-four children aged 0.5–10 years were studied. One hundred and thirty-two gentamicin concentrations (median of four per patient), drawn 0.4–24.6 h after administration of the intramuscular dose, were analysed. The data were fitted by a two-compartment model using the population package NONMEMw. Results: Gentamicin was rapidly absorbed and all concentrations measured within the first 2 h after administration were >8 mg/L (indicating that satisfactory peak concentrations were achieved). Ninetyeight percent of samples measured more than 20 h after the dose were <1 mg/L. The best model included weight, and it was found that high base deficit, high creatinine concentration and low temperature (all markers of hypovolaemic shock) reduced clearance (CL/F). Weight influenced volume of the central (V1/F) and peripheral (V2/F) compartments, and high base deficit reduced V2/F and intercompartmental CL (Q/F). Interindividual variability in CL was 26%, in V1/F 33% and in V2/F and Q/F was 52%. Individual estimates of CL/F ranged from 0.02 to 0.16 (median 0.10) L/h/kg and those of Vss/F from 0.26 to 1.31 (median 0.67) L/kg. Initial half-lives had a median of 1.4 h and elimination half-lives and a median of 14.9 h. Excessive concentrations were observed in one patient who had signs of renal impairment and shock. Conclusions: Although a daily dose of 7.5 mg/kg achieves satisfactory gentamicin concentrations in the majority of patients, patients with renal impairment and shock may be at risk of accumulation with 24 hourly dosing. Further studies of gentamicin pharmacokinetics in this group are now needed to inform future international guideline recommendations

Risk factors associated with the epilepsy treatment gap in Kilifi, Kenya: a cross-sectional study.

BACKGROUND: Many people with epilepsy in low-income countries do not receive appropriate biomedical treatment. This epilepsy treatment gap might be caused by patients not seeking biomedical treatment or not adhering to prescribed antiepileptic drugs (AEDs). We measured the prevalence of and investigated risk factors for the epilepsy treatment gap in rural Kenya. METHODS: All people with active convulsive epilepsy identified during a cross-sectional survey of 232,176 people in Kilifi were approached. The epilepsy treatment gap was defined as the percentage of people with active epilepsy who had not accessed biomedical services or who were not on treatment or were on inadequate treatment. Information about risk factors was obtained through a questionnaire-based interview of sociodemographic characteristics, socioeconomic status, access to health facilities, seizures, stigma, and beliefs and attitudes about epilepsy. The factors associated with people not seeking biomedical treatment and not adhering to AEDs were investigated separately, adjusted for age. FINDINGS: 673 people with epilepsy were interviewed, of whom 499 (74%) reported seeking treatment from a health facility. Blood samples were taken from 502 (75%) people, of whom 132 (26%) reported taking AEDs, but 189 (38%) had AEDs detectable in the blood. The sensitivity and specificity of self-reported adherence compared with AEDs detected in blood were 38·1% (95% CI 31·1-45·4) and 80·8% (76·0-85·0). The epilepsy treatment gap was 62·4% (58·1-66·6). In multivariable analysis, failure to seek biomedical treatment was associated with a patient holding traditional animistic religious beliefs (adjusted odds ratio 1·85, 95% CI 1·11-2·71), reporting negative attitudes about biomedical treatment (0·86, 0·78-0·95), living more than 30 km from health facilities (3·89, 1·77-8·51), paying for AEDs (2·99, 1·82-4·92), having learning difficulties (2·30, 1·29-4·11), having had epilepsy for longer than 10 years (4·60, 2·07-10·23), and having focal seizures (2·28, 1·50-3·47). Reduced adherence was associated with negative attitudes about epilepsy (1·10, 1·03-1·18) and taking of AEDs for longer than 5 years (3·78, 1·79-7·98). INTERPRETATION: The sensitivity and specificity of self-reported adherence is poor, but on the basis of AED detection in blood almost two-thirds of patients with epilepsy were not on treatment. Education about epilepsy and making AEDs freely available in health facilities near people with epilepsy should be investigated as potential ways to reduce the epilepsy treatment gap. FUNDING: Wellcome Trust

A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

<p>Abstract</p> <p>Background</p> <p>Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers.</p> <p>Methods</p> <p>Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days.</p> <p>Results</p> <p>The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (C_max) was 160-200 nM and after 6 hours, the effective concentration (C_eff) was <150 nM.</p> <p>Conclusion</p> <p>Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable C_effof 250-400-nM required to clear malaria infection <it>in vivo</it>. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.</p

Determination of ciprofloxacin in human plasma using high-performance liquid chromatography coupled with fluorescence detection: Application to a population pharmacokinetics study in children with severe malnutrition

Article published in Journal of Chromatography BClinical pharmacokinetic studies of ciprofloxacin require accurate and precise measurement of plasma drug concentrations. We describe a rapid, selective and sensitive HPLC method coupled with fluorescence detection for determination of ciprofloxacin in human plasma. Internal standard (IS; sarafloxacin) was added to plasma aliquots (200uL) prior to protein precipitation with acetonitrile. Ciprofloxacin and IS were eluted on a Synergi Max-RP analytical column (150mm×4.6mm i.d., 5um particle size) maintained at 40 ◦C. The mobile phase comprised a mixture of aqueous orthophosphoric acid (0.025 M)/methanol/acetonitrile (75/13/12%, v/v/v); the pH was adjusted to 3.0 with triethylamine. A fluorescence detector (excitation/emission wavelength of 278/450 nm) was used. Retention times for ciprofloxacin and IS were approximately 3.6 and 7.0 min, respectively. Calibration curves of ciprofloxacin were linear over the concentration range of 0.02–4ug/mL, with correlation coefficients (r2)≥0.998. Intraand inter-assay relative standard deviations (SD) were <8.0% and accuracy values ranged from 93% to 105% for quality control samples (0.2, 1.8 and 3.6ug/mL). The mean (SD) extraction recoveries for ciprofloxacin from spiked plasma at 0.08, 1.8 and 3.6ug/mL were 72.8±12.5% (n = 5), 83.5±5.2% and 77.7±2.0%, respectively (n = 8 in both cases). The recovery for IS was 94.5±7.9% (n = 15). The limits of detection and quantification were 10 ng/mL and 20 ng/mL, respectively. Ciprofloxacin was stable in plasma for at least one month when stored at −15 ◦C to −25 ◦C and −70 ◦C to −90 ◦C. This method was successfully applied to measure plasma ciprofloxacin concentrations in a population pharmacokinetics study of ciprofloxacin in malnourished children.Clinical pharmacokinetic studies of ciprofloxacin require accurate and precise measurement of plasma drug concentrations. We describe a rapid, selective and sensitive HPLC method coupled with fluorescence detection for determination of ciprofloxacin in human plasma. Internal standard (IS; sarafloxacin) was added to plasma aliquots (200uL) prior to protein precipitation with acetonitrile. Ciprofloxacin and IS were eluted on a Synergi Max-RP analytical column (150mm×4.6mm i.d., 5um particle size) maintained at 40 ◦C. The mobile phase comprised a mixture of aqueous orthophosphoric acid (0.025 M)/methanol/acetonitrile (75/13/12%, v/v/v); the pH was adjusted to 3.0 with triethylamine. A fluorescence detector (excitation/emission wavelength of 278/450 nm) was used. Retention times for ciprofloxacin and IS were approximately 3.6 and 7.0 min, respectively. Calibration curves of ciprofloxacin were linear over the concentration range of 0.02–4ug/mL, with correlation coefficients (r2)≥0.998. Intraand inter-assay relative standard deviations (SD) were <8.0% and accuracy values ranged from 93% to 105% for quality control samples (0.2, 1.8 and 3.6ug/mL). The mean (SD) extraction recoveries for ciprofloxacin from spiked plasma at 0.08, 1.8 and 3.6ug/mL were 72.8±12.5% (n = 5), 83.5±5.2% and 77.7±2.0%, respectively (n = 8 in both cases). The recovery for IS was 94.5±7.9% (n = 15). The limits of detection and quantification were 10 ng/mL and 20 ng/mL, respectively. Ciprofloxacin was stable in plasma for at least one month when stored at −15 ◦C to −25 ◦C and −70 ◦C to −90 ◦C. This method was successfully applied to measure plasma ciprofloxacin concentrations in a population pharmacokinetics study of ciprofloxacin in malnourished children

Fosphenytoin for seizure prevention in childhood coma in Africa: a randomized clinical trial.

PURPOSE: We conducted a double-blind trial to determine whether a single intramuscular injection of fosphenytoin prevents seizures and neurologic sequelae in children with acute coma. METHODS: We conducted this study at Kilifi District Hospital in coastal Kenya and Kondele Children's Hospital in western Kenya. We recruited children (age, 9 months to 13 years) with acute nontraumatic coma. We administered fosphenytoin (20 phenytoin equivalents/kg) or placebo and examined the prevalence and frequency of clinical seizures and occurrence of neurocognitive sequelae. RESULTS: We recruited 173 children (median age, 2.6 [interquartile range, 1.7-3.7] years) into the study; 110 had cerebral malaria, 8 had bacterial meningitis, and 55 had encephalopathies of unknown etiology. Eighty-five children received fosphenytoin and 88 received placebo. Thirty-three (38%) children who received fosphenytoin had at least 1 seizure compared with 32 (36%) who received placebo (P = .733). Eighteen (21%) and 15 (17%) children died in the fosphenytoin and placebo arms, respectively (P = .489). At 3 months after discharge, 6 (10%) children in the fosphenytoin arm had neurologic sequelae compared with 6 (10%) in the placebo arm (P = .952). CONCLUSION: A single intramuscular injection of fosphenytoin (20 phenytoin equivalents/kg) does not prevent seizures or neurologic deficits in childhood acute nontraumatic coma

Population pharmacokinetics of intramuscular gentamicin administered to young infants with suspected severe sepsis in Kenya

Aims To determine the population pharmacokinetics of intramuscular (i.m.) gentamicin in African infants with suspected severe sepsis. Methods Samples were withdrawn 1 h after a single i.m. injection of 8 mg kg(-1) gentamicin and the next morning prior to any further dosing. Concentration-time data were analysed with the population pharmacokinetic package NONMEM. Data were fitted using a one-compartment model with a log-normal model for interindividual variability and an additive residual error model. The influence of a range of clinical characteristics was tested on the pharmacokinetics of intramuscular gentamicin and the effect of incorporating interindividual variability on bioavailability was examined. Results The data set comprised 107 patients and 203 concentrations. Peak concentrations ranged from 3.0 mg L-1 to 19.8 mg L-1 (median 10.6 mg L-1) and 'next day' samples from 0.3 mg L-1 to 6.2 mg L-1 .The best models were clearance/bioavailability (CL) (L h(-1)) = 0.0913 x weight (kg) x (age (days) + 1)/11)(0.130) and volume of distribution/bioavailability (V) = 2.02 x (1 + 0.277 x (weight -3)). Therefore, an infant with the median weight of 3 kg and age 10 days would have a predicted CL of 0.274 L h(-1) and V of 2.02 L. Interindividual variability in CL was 40% and in V was 42%. This model required a term for covariance between CL and V. When variability in bioavailability was introduced as an alternative model, interindividual variability in CL was 22%, in V 18% and in relative bioavailability 36%. Conclusions Intramuscular administration of 8 mg kg(-1) gentamicin daily to infants gives mean 1 h peak concentration of 10.6 mg L-1 and a trough concentration of less than 2 mg L-1. Wide variability in the peak concentration may reflect variable absorption rate or bioavailability

Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

AIMS: Phenobarbital is commonly used to treat status epilepticus in resource-poor countries. Although a dose of 20 mg kg(-1) is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15-mg kg(-1) intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus. METHODS: Twelve children (M/F: 11/1), aged 7-62 months, received a loading dose of phenobarbital (15 mg kg(-1)) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg(-1) at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l(-1) for 72 h. RESULTS: All the children achieved plasma concentrations above 15 mg l(-1) by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, infinity)]: 4259 (3169, 5448) mg l(-1).h, t(1/2): 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg(-1) h(-1), Vss: 0.8 (0.7, 0.9) l kg (-1), CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n= 6) and Cmax: 19.9 (17.9-27.9) mg l(-1). Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg(-1) followed by two maintenance doses of 2.5 mg kg(-1) at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l(-1) for 72 h. CONCLUSIONS: Phenobarbital, given as an i.v. loading dose, 15 mg kg(-1), achieves maximum plasma concentrations of greater than 15 mg l(-1) with good clinical effect and no significant adverse events in children with severe falciparum malaria. A maintenance dose of 2.5 mg kg(-1) at 24 h and 48 h was predicted to be sufficient to maintain concentrations of 15-20 mg l(-1) for 72 h, and may be a suitable regimen for treatment of convulsions in these children