Vincent CROIXMARIE, Adrien TESSIER
Clinical Pharmacometrics - Quantitative Pharmacology, Servier, Suresnes, France
Objectives:
An important unmet need exists in Intermediate-High Risk Acute Pulmonary Embolism suffering patients. A phase 2 study to find the appropriate dose of a drug candidate in this indication on top of heparin was planned. The targeted population experiences an acute renal impairment originating from lack of perfusion due to the pulmonary circulation blockade by a clot. As this drug candidate is mainly excreted unchanged by kidney, a dose adaptation strategy has been proposed. Additionally, we were able to inform dose level choice. The route of administration is intra venous (IV) with a bolus for 20 % of the total amount followed by 6-hours infusion for the remaining 80 %.
Methods:
An existing phase 1 population PK model in healthy volunteers has been used. The final model was a 3-compartment model parameterized by volumes and clearances. A combined proportional and additive error model together with Inter-Individual variability estimated on V1, V2, CL and Q2 best described the data. Two covariates – weight on elimination clearance and dose on Q2 – were included in the model. A clinical trial simulation (CTS) approach using this model combined with the expected characteristics of the targeted phase 2 population has been used.
In the targeted population [1,2] approximately 60 % of the participants are expected to have a mild (estimated glomerular filtration rate (eGFR) of [60; 90[ mL/min) acute renal impairment (RI) – respectively 40 % a moderate RI (eGFR of [30; 60[ mL/min). Our reference population in the subsequent work was the mild RI subjects. The dose selection has been based on drug concentration threshold 10 hours (C10h) after drug intake. This concentration should be maintained at least in 90% of the reference population. Our dose adaptation strategy has then been assessed in order to keep exposure of moderate RI patients close to the reference population one. Three scenarios has been evaluated and compared: no adaptation, adaptation for moderate RI patients as a single category (2 intervals total) or adaptation with 3 intervals (moderate RI interval being split in two: [30; 45[ and [45; 60[ mL/min clearance).
The main hypotheses were (i) an absence of difference between HV and patients when considering significant covariates (i.e. creatinine clearance and weight) and (ii) that the eGFR extrapolation from HV for mild and moderate renal impaired function is valid.
Results:
The intermediate scenario with only 2 intervals did not corrected C10h distribution for the [30; 45[ mL/min eGFR subgroup to the reference population level’s. Therefore, the 3 intervals dose adjustment strategy has been chosen. With C10h thresholds of 7.5 ng/mL and 100 ng/mL for lowest and highest dose choice respectively, the recommended doses were 1.6 and 20 mg respectively. Two intermediate dose levels (4.8 and 10.5 mg) have been also chosen by the clinicians. Because of our strategy, the PK profile overlap of two adjacent dose levels is markedly reduced when applying a 3 intervals adaptation scenario. This will further help study outcome analysis.
Conclusions:
The proposed dose adaptation strategy has been endorsed by the study team. The lowest and the highest recommended dose have been chosen for the phase 2 study.
References:
[1] Altınsoy et al (2016). Prognostic Value of Renal Dysfunction Indicators in Normotensive Patients With Acute Pulmonary Embolism. Clinical and Applied Thrombosis/Hemostasis 2017, Vol. 23(6) 554-561.
[2] Kostrubiec et al (2019). The Prognostic Value of Renal Function in Acute Pulmonary Embolism—A Multi-Centre Cohort Study. Thromb Haemost 2019;119:140–148.
Reference: PAGE 30 (2022) Abstr 10034 [www.page-meeting.org/?abstract=10034]
Poster: Drug/Disease Modelling - Other Topics