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

Abstract

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, ∞) ]: 4259 (3169, 5448) mg l−1.h, : 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.

Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsions

“…If the convulsions continued following administration of the first‐line drugs (MDZ or paraldehyde), then phenytoin (Faulding Pharmaceuticals Plc., UK) was administered at a loading dose (18 mg kg −1 ) as an IV infusion over 20 min, followed by a maintenance dose (2.5 mg kg −1 12 hourly) [37]. At 30 min, if the convulsions still persisted, phenobarbital (100 mg ml −1 ; Lab RENAUDIN, France) was administered IV as a loading dose (15 mg kg −1 ) infused over 20 min, followed by maintenance doses (2.5 mg kg −1 ) at 24 and 48 h [38].…”

Effectiveness of Non-benzodiazepine Antiepileptic Drugs in Benzodiazepine-resistant ‎Convulsive Status Epilepticus

“…Phenobarbital has a long half-life and significant cardiorespiratory depressant effects with similar dosing as phenytoin. Four non-controlled studies [20][21][22][23] varied in their study populations investigated the tolerance of IM phenobarbital and its prophylactic effects on seizure frequency reported no notable adverse effects, apart from a tendency of phenobarbital to deepen coma or render patients sleepy that was identified in the Kuile et al (1992) [20] study or to experience respiratory depression as in Kokwaro et al (2003) study [21]. Direct comparisons of intravenous phenobarbital and valproate were reported by Malamiri et al [24] among children with convulsive SE (CSE) and acute prolonged convulsive seizures; higher doses or fast IV rate may result in higher blood-drug levels sooner, which may cause serious adverse events.…”

Physiologically-based Pharmacokinetic (PBPK) Modeling for Prediction of the Optimal Dose Regimens of Quinine and Phenobarbital Co-administration in Adult Patients with Cerebral Malaria and Seizures

“…phenobarbital (15 mg kg -1 or 900 mg total dose for the average 60 kg body weight, IV infusion over 30 minutes) is given as a single dose 6 hours after the first dose of quinine (average time of occurrence of seizure after admission) [33]. The scenario-II applies for patients who have continuous seizures; phenobarbital at a loading dose of 15 mg kg -1 or 900 mg total dose for the average 60 kg body weight IV infusion over 30 minutes, followed by the maintenance dose of 1.5 mg kg -1 day -1 (1-3 mg.kg -1 day -1 ) or 90 mg total dose for average 60 kg body weight IV infusion over 30 minutes [33] is given every 24 hours, starting 6 hours after the first dose of quinine until 72 hours. The time of simulation and seizure frequency was based on the clinical report [34].…”

“…The optimal dosage of phenobarbital were proposed based on the therapeutic rage of phenobarbital: C max  40 mg.L -1 [36], and C trough  15 mg.L -1 [33]. The predicted pharmacokinetic parameters are presented as mean (95% confidence interval or CI).…”