Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for “non-lactating” adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (C_max) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.

The interest in the development and therapeutic application of long-acting injectable products for chronic or long-term treatments has experienced exponential growth in recent decades. TV-46000 (Uzedy, Teva) is a long-acting subcutaneous (sc) injectable formulation of risperidone, approved for the treatment of schizophrenia in adults. Following sc injection, the copolymers together with risperidone precipitate to form a sc depot under the skin to deliver therapeutic levels of risperidone over a prolonged period of either 1 month or 2 months, depending upon the dose. This work presents the strategy and the results of the physiologically-based pharmacokinetic (PBPK) modeling and establishing of in vitro–in vivo correlation (IVIVC) for the prediction of TV-46000 pharmacokinetic profile in humans, using in vitro release, intravenous (iv), and sc single-dose pharmacokinetic data in beagle dogs. The resulting simulated TV-46000 PK profile in humans showed that the shape of the predicted risperidone and its active metabolite 9-OH-risperidone PK profiles was different from the observed one, thus suggesting that the TV-46000 release profile was species-dependent and cannot be directly extrapolated from dog to human. In conclusion, while level A IVIVC cannot be claimed, this work combining PBPK and IVIVC modeling represents an interesting alternative approach for complex injectable formulations where classical methods are not applicable.

Background: TV-46000 (Uzedy, Teva), a long-acting subcutaneous antipsychotic, is an injectable formulation of risperidone and is approved by the FDA for the treatment of schizophrenia in adults. Its innovative copolymer-based drug delivery depot technology (licensed from MedinCell, Jacou, France) allows for plasma concentrations of the total active moiety of risperidone (TAM) to reach clinically relevant levels within 6–24 h and the maintenance of these therapeutic levels with monthly and bimonthly dosing regimens. Objective: As part of the development program for TV-46000, the effect of extrinsic factors of manipulation on the site of injection, and on the pharmacokinetic (PK) profile of TAM following TV-46000 administration was evaluated. Methods: Studies were conducted assessing the effect of heat and rubbing with male Gottingen minipigs and the effect of rubbing with male beagle dogs. A pilot clinical study in healthy volunteers was performed to evaluate the effect of rubbing. Results: These investigations showed that heating or rubbing of the TV-46000 sc injection site immediately post-injection had no clinically meaningful impact on safety and no burst or uncontrolled release was evident. Furthermore, no impact of injection site manipulation on TAM exposure was observed after depot formation (≥0.5 h post-injection). Conclusions: The observed similarity in findings between the animal and human studies supports the suitability of animal models for evaluation of the effect of extrinsic factors on injection sites and its translatability to clinical settings.

Background: TV-44749 is a subcutaneous (sc) long-acting injectable (LAI) formulation of olanzapine that recently demonstrated efficacy and safety as a treatment for schizophrenia in adults without the occurrence of post-injection delirium/sedation syndrome (PDSS) in the phase 3 SOLARIS trial (NCT05693935). TV-44749’s sc route of administration and formulation were designed to provide prolonged olanzapine release over a monthly dosing interval and to avoid the risk of post-injection delirium/sedation syndrome (PDSS). It was designed as a copolymer in situ-forming depot technology to provide a LAI formulation that could withstand physiological and environmental factors that could affect controlled-release kinetics. Methods: To evaluate the robustness of the TV-44749 formulation, an in vitro release (IVR) study in human plasma was conducted, comparing TV-44749 to the commercially available intramuscular (im) long-acting injection formulation of olanzapine pamoate monohydrate. In addition, in vivo studies in rats were conducted to assess the effect of injection site manipulation following TV-44749 sc injection on olanzapine release from the depot. Results: The IVR study showed that upon contact with human plasma, copolymers comprising TV-44749 formulation instantly precipitate and form a solid matrix that entraps olanzapine particles. This prevents an uncontrolled release of olanzapine. Additionally, in vivo rat studies found that manipulation of the injection site after TV-44749 administration, by either heating or rubbing at different time-points, resulted in no meaningful effect on overall olanzapine exposure. Conclusions: The presented findings support the robustness of the TV-44749 formulation in maintaining controlled-release properties, even under conditions that could otherwise compromise release performance.