Synthesising pragmatic and optimal design: NAPPA - a paediatric penicillin population pharmacokinetic study
Charlotte I. S. Barker (1, 2), Mike Sharland (1), Mark A. Turner (3), Joe F. Standing (2)
(1) Paediatric Infectious Diseases Research Group, Infection and Immunity Research Institute, St George’s University of London (2) Infectious Diseases and Microbiology, Institute of Child Health, University College London (3) University of Liverpool, Department of Women's and Children's Health, Institute of Translational Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK
Objectives: The Neonatal and Paediatric Pharmacokinetics (PK) of Antimicrobials study, NAPPA, is a multicentre population PK study evaluating six penicillins used in routine care (amoxicillin/ampicillin/benzylpenicillin/coamoxiclav/flucloxacillin/piptazobactam). The protocol uses opportunistic (‘scavenged’) sampling strategies, which can be supplemented by optimally timed samples using a non-invasive method (e.g. arterial catheter sampling). The NAPPA optimal design strategy aimed to identify optimum timing recommendations grouped across all participant age-groups, from infants to adolescents.
Methods: The optimal design exercise was implemented with PopED software using the D-optimality criterion. A literature search was first undertaken to identify published population PK models of the relevant penicillins in order to select an appropriate model on which to base the optimal design. Modelled participants’ ages were allocated to the mid-point of each age-group, linked with mean weight-for-age. A representative dosing strategy was selected: single intravenous flucloxacillin bolus of 25mg/kg. Participant number per group was set at the maximum study target. The additive residual error was adjusted to reflect anticipated assay limits: 2.5mg/L. Three optimal sampling times were predicted. Sampling windows were identified to increase the feasibility of sampling in routine healthcare.
Results: A three compartment PK model based on flucloxacillin PK data was selected from the literature [1]. A maturation function was added to the clearance parameter [2], to account for changes relating to age and weight:
CLA = CL*(Weight/70)^0.75*(Age^3.4/(47.7^3.4+Age^3.4))
The D-optimal design results were as follows, with the associated sampling windows selected:
|
Sample number |
1 |
2 |
3 |
|
Optimal time (hours post dose) |
0.26 |
1.67 |
3.54 |
|
Sample window |
0.17-0.50 |
1.42-2.25 |
3.00-4.00 |
The impact of these sampling windows resulted in 84% normalized efficiency.
Conclusions: D-optimality design in PopED was used to select optimal timing recommendations for a penicillin PK study in different age-groups, from infants to adolescents. The feasibility of the recommendations was enhanced by selecting practical timing windows to reflect the flexibility needed in routine healthcare for study implementation. Future work will consider whether the recruitment targets within different age-groups can be adjusted to reflect the maturation of clearance associated with changes in age and weight over time.
References:
[1] Landersdorfer CB, Kirkpatrick CM, Kinzig-Schippers M, Bulitta JB, Holzgrabe U, Drusano GL, Sörgel F. Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin. Antimicrob Agents Chemother. 2007; 51(9): 3290-7.
[2] Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009; 24(1): 67-76.