Helene Karcher, Amy Racine
Novartis Pharma AG
Objectives: Therapeutic drug monitoring (TDM) enables to adjust dosage to the needs of a particular patient. It circumvents inter-patient variability in PK though it cannot palliate to intra-patient variability [1]. Its particular usefulness in widening the therapeutic window for a new drug A used in combination was explored trough modeling of Phase II data.
The Phase II trial combined drugs A and B at various levels of fixed doses (drug A) or target concentration ranges (drug B) and explored the efficacy endpoint in terms of event rate. Safety profiles for both drugs had been previously characterized.
Methods:
1. A range of mixed-effects models were fitted to drug A’s plasma trough concentration data, including inter-patient variability to characterize the relationship between drug A’s dose and exposure. This model was used to investigate TDM feasibility and its impact on PK variability.
2. A mixed-effects exposure – response model was built on longitudinal trough concentrations for both drugs and event rate of the efficacy endpoint. The model extracted the exposure-event probability relationship and took into account inter-patient variability in event probability under same levels of A and B.
3. Simulations using the above models enabled to quantify the benefits of TDM on drug A in terms of PK variability reduction compared to fixed dose regimens. The frequency of dose changes for drugs was also investigated.
Results: A log-linear model structure with a random effect on intercept yielded the best fit of the dose-trough data in terms of AIC and BIC. Inter- and intra-patient variability in drug A troughs was found to change over time. At steady-state, the values were ~64% inter-patient and ~48% intra-patient variability. The smallest possible TDM window for drug A troughs at steady-state was derived from these values.
Event probability was found to clearly depend on drug A exposure in the first trial period. The rarity of late events prevented the establishment of such a relationship at steady-state. While no efficacy gain from increasing drug B levels could be extracted within the explored range, drug B was indispensable to maintain efficacy since higher event rates were observed in a previous trial without B.
A simulation showed that TDM enabled to maintain trough levels within a defined window after only a few dose adjustments. The starting dose of A was found to have an impact on the final trough distribution though it had no impact on the percentage of troughs that remained outside of range at steady state.
Conclusions: Therapeutic drug monitoring was shown to be feasible and useful for drug A in combination with drug B.
References:
[1] Matthews, I., Kirkpatrick, C. and Holford, N. (2004), Quantitative justification for target concentration intervention – parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides. British Journal of Clinical Pharmacology, 58: 8–19.
Reference: PAGE 21 () Abstr 2569 [www.page-meeting.org/?abstract=2569]
Poster: Other Modelling Applications