Population pharmacokinetic modeling of cisplatin in patients with small cell lung cancer using informative priors
Jurij Zdovc (1), Mihaela Vaupotič (1), Lea Knez (2), Tanja Čufer (2), Gregor Marolt (3), Tomaž Vovk (1), Iztok Grabnar (1)
(1) University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia, (2) University Clinic of Respiratory and Allergic Diseases Golnik, Golnik, Slovenia, (3) University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia
Objectives: The small cell lung cancer (SCLC) is the most aggressive type of lung cancer and is diagnosed in around 15% of all lung cancer cases. Cisplatin in combination with etoposide is recommended as a standard, first line of treatment for the extensive stage SCLC. Cisplatin is associated with dose-limiting side effects such as nephrotoxicity, nausea, vomiting and ototoxicity [1, 2]. A two-compartment model was previously reported to describe the pharmacokinetics of cisplatin when administered in a form of intravenous infusion. The dosing is conventionally adjusted with respect to the body surface area (BSA), however, BSA alone cannot explain all inter-individual variability. Moreover, estimated pharmacokinetic parameters reported from several population pharmacokinetic studies vary substantially, leading to a high variability in the estimated exposure [3–7]. Thus we aim to assess the exposure of SCLC patients to cisplatin with population pharmacokinetic approach, comparing several clinical studies.
Methods: This was a prospective clinical study in 17 patients with SCLC, treated with cisplatin-etoposide at the University Clinic of Respiratory and Allergic Diseases Golnik. Cisplatin dose was based on BSA (55 – 85 mg/m2; calculated with the Mosteller equation [8]) and was administered as a 1-hour infusion on the second day of each treatment cycle. Treatment cycle was repeated every three weeks. Plasma samples (n = 100) from total of 58 treatment cycles were collected between 7 minutes and 7 hours after the start of the infusion. Population pharmacokinetic analysis was performed using the nonlinear mixed-effects modelling software NONMEM® 7.3. Based on the previous studies we analyzed a one- and two-compartment model with and without the informative priors from published population pharmacokinetic studies [3–5]. Priors were included in the model as a $PRIOR block in the form of NWPRI file. From the estimated individual cisplatin clearance (CL) and the dose administered we calculated the AUC for every cycle for every patient (AUC = Dose/CLi). The study was approved by the Slovenian Ethics Committee for Research in Medicine (approval ref. no. 0120-220/2018/3) and was carried out according to the Helsinki declaration.
Results: There were 6 females and 12 males in the study group. Median age was 63 years and median creatinine clearance was 85.1 mL/min, which indicated a normal renal function. The medians of body weight and BSA of our patients were 84 kg and 2.0 m2, respectively, which was higher than in the groups of reported clinical studies. Without the use of priors, we were able to fit a one-compartment model to our data. However, considering our small sample size and low power of our study it was possible our data was uninformative. Therefore, the use of a one-compartment model could be biased, since the pharmacokinetics of cisplatin is usually described by a two-compartment model. Using the informative prior distribution of pharmacokinetic parameters from three clinical studies, the structural model was a two-compartment model. Estimate of CL depended on the study from which the prior was used. However in all cases the final estimate of CL was higher than initial prior estimate, with final estimates ranging between 28.9 L/h and 45.1 L/h. This could imply our patients had a higher CL than patients from other studies. Moreover, goodness-of-fit indicated all models with priors overestimated the plasma cisplatin concentrations. Besides, CL estimated with a base one-compartment model without priors was 65 L/h. This is in accordance with the hypothesis that our patients had a higher CL. The underlying reason for deviations is currently unknown, however, we hypothesize higher BSA of our patients could be involved. The disease could be a factor as well, since this is a first study of cisplatin in patients with SCLC. From this perspective, the results indicate our patients were underexposed to cisplatin. The estimated individual exposure of our patients to cisplatin across all models ranged between 1.55 mg*h/L and 4.81 mg*h/L.
Conclusions: Despite cisplatin has been used for several years, the variability in pharmacokinetics and patients’ exposure is still high. Further studies are necessary to identify additional factors influencing exposure of patients with SCLC.
References:
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