H. Maxime Lagraauw (1), Marita Prohn (1), Lars Lindbom (1), Anne Santerre Henriksen (2, 3)
(1) qPharmetra LLC, Nijmegen, The Netherlands, (2) Utility Therapeutics, Cheshire, UK, (3) Maxel Consulting ApS, Jyllinge, Denmark
Introduction: A population pharmacokinetic (PopPK) model was developed to characterize mecillinam (MEC) pharmacokinetics (PK) and urine exposure after intravenous (IV) administration of MEC or after oral (PO) administration of its prodrug pivmecillinam (PIV) in healthy subjects and patients with renal impairment (RI) or infections. MEC is a β-lactam antibiotic with a broad spectrum of activity against most Gram-negative bacteria. The derived model was used to investigate the impact of various PIV treatment regimens and covariate scenarios on plasma exposure and urine excretion, and to perform probability of target attainment (PTA) simulations in support of dose justification for the treatment of uncomplicated urinary tract infection (uUTI).
Methods: The analysis was based on MEC PK data obtained in plasma, serum, and urine in fifteen clinical studies performed between 1975 and 1999. The analysis dataset included a total of 3964 plasma or serum concentrations and 989 urine excretion samples obtained in 228 subjects. Those 228 subjects consisted of 172 healthy volunteers, 23 patients with infections (uUTI, Gram-negative infection, typhoid, or paratyphoid fever), and 33 patients with various degrees of renal impairment (RI). Subjects were treated with single or multiple doses of MEC (IV, 200-1410 mg) or PIV (PO, 137-500 mg).
Results: MEC PK profiles in plasma and urine were well characterized by a 2-compartment distribution model with first-order renal elimination and nonlinear non-renal elimination. Oral absorption of PIV was best described using a single (Erlang) transit compartment. The residual variability model included a proportional error model for the plasma data and a combined additive and proportional error model for the urine data. Interindividual variability was included on CL, V1, V2, Km, Ka and F1. The PK model included parameter-covariate relationships for WT on all clearance and volume parameters (with fixed allometric exponents of 0.75 and 1), a nonlinear dose effect on bioavailability, formulation effects on Ka, food effects on both Ka and F1, and effects of renal function on both CL and Km. The reduced bioavailability at higher dose levels resulted in a predicted 1.4 fold-increase in MEC exposure when doubling the PIV PO dose from 200 to 400 mg. MEC exposure was predicted to be higher in both plasma and urine in patients with severe RI, with 3.1 and 3.8-fold higher AUC0−12 for a 200 mg dose at creatinine clearance (CLcr) values of 20 and 10 mL/min vs. 90 mL/min, and 3.8 and 3.4-fold higher trough concentration during a dose interval (Ctrough) in urine. Subjects with a high body weight (110 kg) were predicted to have a 52% and 33% lower MEC Ctrough in plasma and urine after administration of 200 mg PIV in comparison to subjects with a typical body weight of 70 kg, respectively. Similarly, MEC exposure (AUC0−12h) is predicted to be 48% and 14% higher in plasma and urine in subjects with a low body weight (50 kg). For the clinically relevant regimens these increases are well within an exposure range previously observed and deemed safe. The final PopPK model was used to simulate 2500 individual plasma and urine PK profiles after oral administration of 200 mg PIV BID or TID or 400 mg BID and two urine voiding frequencies, every 3h or every 45 minutes. For each regimen and voiding frequency combination, the PTA was predicted across a range of values of the PD target, the percentage of a 24h time period that the unbound drug concentration exceeds the MIC (fT>MIC). PTA simulations for the proposed dosing regimen of 200 mg TID predicts up to 70% fT>MIC for the clinical and laboratory standards institute (CLSI) susceptibility breakpoint of 8 mg/L in 90% of the population for a voiding frequency of 45 min.
Conclusions: MEC plasma and urine PK were well characterized by a 2-compartment distribution model with first-order renal and nonlinear non-renal elimination. The oral PIV absorption was best described using a single transit compartment. PTA simulations were supportive of a 200 mg TID dosing regimen.
Reference: PAGE 30 (2022) Abstr 10084 [www.page-meeting.org/?abstract=10084]
Poster: Drug/Disease Modelling - Infection