Model Based Extrapolation Approach Driving a Streamlined Clinical Development Plan for Inhaled Oxytocin
Sarah Siederer1, Shuying Yang2, Kimberley Hacquoil3, Kelly M. Mahar4 Misba Beerahee1
1Clinical Pharmacology Modelling and Simulation Department, GSK, Stevenage, UK, 2Clinical Pharmacology Modelling and Simulation Department, GSK, Stockley, UK, 3Clinical Statistics, GSK, Stevenage, UK; 4Clinical Pharmacology Modelling and Simulation Department, GSK, Upper Merion, US
Objectives: To characterise integrated population (Pop) PK models that describe the disposition of oxytocin (Oxy) following intravenous (IV), intramuscular (IM) and a novel oral inhaled (IH) administration to healthy non-pregnant women (HNPW). These models will be used for the quantitative assessment of systemic comparability to extrapolate clinical safety and efficacy following approved routes (IM/IV) to a novel oral IH route for Oxy. This IH formulation is under development as an an affordable product for low/middle income countries (studies sponsored by GlaxoSmithKline in partnership with Monash University) for the prevention of Postpartum Haemorrhage (PPH).
Methods: A framework for integrated Pop PK models was developed using PK data obtained following IV (n=21), IH (n=15) and IM (n=26) Oxy to HNPW across 2 completed clinical studies (planned post hoc analysis). The IV data were used to estimate the disposition parameters which were then fixed when modelling the IM and IH data. Different absorption models (1st/zero order/Weibull) were tested to adequately characterise the initial time course of drug levels following IM and IH dosing. Model qualification approaches were conducted including the posterior predictive checks. Based on these models, clinical trial simulations will be conducted to identify optimal study designs including sample size, dose selection, decision criteria and population, and to evaluate the probability of reaching the required therapeutic systemic exposure. Modelling was implemented in NONMEM V7.2 or above.
Results: This analysis is first to describe the Pop PK of Oxy after IV, IM and IH dosing in HNPW. A 3-compartment disposition model with 1st order elimination and additive residual error based on log- transformed concentrations adequately described the PK of Oxy (CLIV=37L/h, Vdiv=13L). The multi-phase absorption models were used to characterise the IM (bioavailability (F)~30%) and IH (F<2%) PK. Model diagnostics including goodness of fit, visual and posterior predictive checks indicated the adequacy of the models. An important application of these models will be to support the extrapolation from the IM to IH dosing route by bridging the systemic exposure associated with safety & efficacy.
Conclusions: Model based drug development could be useful to extrapolate to a different route of administration with the potential to make this IH product available in PPH where IV and IM access is limited due to storage and skilled healthcare professional requirements.