Khaled Abduljalil, Trevor N Johnson, Masoud Jamei
Certara UK, Simcyp Division
Objectives: Drugs taken by breastfeeding mothers can be passed onto infants through milk. Therefore, it is important to have reliable estimates of the amount of drugs passed to infants through breastfeeding. However, currently a physiological model-informed approach is not available yet. Physiologically-Based Pharmacokinetic (PBPK) models can be used to predict drug concentrations in breastmilk and subsequent neonatal exposure. The objective of this work is to use PBPK modelling approach to predict the maternal plasma, milk exposure, and the daily infant dose (DID) after maternal intake of 750 mg of Ciprofloxacin using the Simcyp Simulator.
Methods: The default previously qualified library compound model of ciprofloxacin in the Simcyp Simulator V19 was used. The compound is modelled using a full PBPK distribution model based on the Rodgers & Rowland’s method [1]. The Advanced Dissolution, Absorption and Metabolism (ADAM) absorption model was used to describe the absorption process. The model was used to predict ciprofloxacin PK in 10 trials of 10 lactating women aged 27 years olds after 750mg oral administration to mimic the reported clinical data [2]. There is no evidence that Ciprofloxacin is substrate of transporters. Thence, a one-compartment tissue can be used to represent the breast. For this purpose, the perfusion-limited mode of the ‘additional compartment’ in the Simcyp Simulator was used. To determine the drug concentration in milk the milk to plasma partition coefficient (kp) for this compartment was optimised to recover the observed milk concentration. The predicted average milk concentration was used to calculate the DID using milk volume intake of 150 and 200 mL/day/Kg of neonatal weight. The predicted DID for the 200 mL/kg milk intake was used within the Simcyp Paediatric Simulator V19 to predict plasma exposure in one month old neonates (n=100).
Results: The developed PBPK model showed good agreement with both maternal plasma and milk concentration profiles. The calculated average±SD (and Geomean (90%predictive intervals)) DIDs were 0.124±0.033 (0.120 (0.115-0.126) and 0.166±0.044 (0.160 (0.153-0.168) mg/day/Kg of neonatal body weight for milk intake of 150 and 200 mL/day/Kg of neonatal weight, respectively. The 0.166 mg/kg infant dose resulted in an average ±SD AUC∞ of 0.30±0.08 mg/L*h, Cmax of 0.11±0.01 mg/L and oral clearance of 2.39±0.80 L/h.
Conclusions: PBPK models developed using prior drugs physicochemical properties and systems parameters was used for investigating the drug exposure in milk and to determine the expected daily infant dose taking into account inter-subject variability in maternal plasma and milk concentrations. This approach can be used for other drugs and explore different scenarios affecting milk exposure, such as drug-drug interactions and dose adjustment. In terms of neonatal exposure, the predicted DID can be used within paediatric PBPK models to predict drug exposure in individual organs relevant for therapeutics and risk assessments.
References:
[1] Rodgers T et al. J Pharm Sci. 2006;95(6):1238-57.
[2] Giamarellou H et al. Am J Med. 1989;87(5A):49S–51S.
Reference: PAGE () Abstr 9249 [www.page-meeting.org/?abstract=9249]
Poster: Drug/Disease Modelling - Absorption & PBPK