Population Pharmacokinetics and Use of Monte Carlo Simulation To Determine Optimal Dosing Regimen of Oral Ciprofloxacin in Paediatric Patients with Severe Malnutrition
Ungphakorn W(1), Thuo N(2), Muturi N(2), Karisa J(2), Muchohi S(2), Kokwaro G(3,4), Thomson AH(1,5), Maitland K(2,6)
(1)SIPBS, University of Strathclyde, Glasgow, (2)KEMRI-Wellcome Collaborative Programme, Kilifi, Kenya, (3)Dept of Pharmaceutics and Pharmacy Practice, University of Nairobi, Nairobi, Kenya, (4)Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Nairobi, Kenya, (5)Pharmacy Dept, Western Infirmary, Glasgow, (6)Imperial College, London
Objectives: Oral ciprofloxacin has been considered as an alternative antimicrobial agent for severely malnourished children. However, to date, there are no pharmacokinetic data in this patient population and an appropriate dosing regimen is not well defined. The aims of this study were to determine the influence of clinical characteristics on the population pharmacokinetics of oral ciprofloxacin in paediatric patients with severe malnutrition and consequently to define the optimal dosing regimen.
Methods: The study was conducted at Kilifi District Hospital, Kenya. Ciprofloxacin 10 mg/kg was administered 12 hourly for 48 hours and up to 4 samples were withdrawn at various times. The data were analysed with NONMEM [1] Version VI using FOCE with interaction. First order, zero order, and transit compartment absorption models were compared. Allometric relationships between oral clearance (CL/F) and volume of distribution (V/F) and weight were included in the base model. A range of clinical characteristics was examined for their influence on ciprofloxacin pharmacokinetics. A 10,000-patient Monte Carlo simulation was performed to determine the probability of achieving the target AUIC of at least 125 and 35 for gram-negative and gram positive organisms, respectively. The cumulative fraction of response (CFR) were calculated [2].
Results: The data comprised 202 ciprofloxacin concentration measurements from 52 infants and children aged 8 to 102 months. A one compartment model with first order absorption and a lag adequately described the data. A combination of high mortality risk and serum sodium concentration provided the best fit for CL/F and sodium concentration for V/F. Inclusion of these factors reduced between subject variability in CL/F from 50% to 38% and in V/F from 49% to 43%. Absorption rate was poorly estimated and highly variable. Bootstrap, pc-VPC and npde results were satisfactory. With the current regimen, the breakpoint MIC was <0.06 mg/L for gram-negative organisms and was <0.25 mg/L for gram-positive organisms. The overall responses were >75% against Salmonella spp., K. pneumoniae, and E. coli but least than 50% against P. aeruginosa and S. pneumoniae. Higher doses provided a little advantage.
Conclusions: The findings suggest that the pharmacokinetics of oral ciprofloxacin in malnourished children are influenced by weight, serum sodium, and presence of high mortality risk. Oral ciprofloxacin with a dose of 20 mg/kg/day achieves adequate concentrations for some organisms but other drugs should be considered for P. aeruginosa and S. pneumoniae infections in this patient population.
References:
[1] Beal, S. L., L. B. Sheiner, et al. (1989-2006). NONMEM user's Guides. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Drusano, G. L., S. L. Preston, et al. (2001). Use of preclinical data for selection of a phase II/III dose for evernimicin and identification of a preclinical MIC breakpoint. Antimicrob Agents Chemother 45: 13-22.
