Shankar Lanke, Susan E. Shoaf
Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ
Objectives:Tolvaptan has been shown to slow the progression of kidney enlargement and the rate of kidney function decline in patients with autosomal dominant polycystic kidney disease (ADPKD) [1]. The objective is to develop a population pharmacokinetic (Pop PK) model to describe tolvaptan pharmacokinetics in ADPKD subjects following oral administration.
Methods:Pop PK analysis included data from 1091 subjects with 7335 observations split into dense and sparse data. The Pop PK model was developed using NONMEM version 7.3.0 and the stochastic approximation expectation maximization estimation method. A one and two compartmental models (CM) with first and zero order absorption, first-order elimination were evaluated to determine the structural model. Full covariate analysis was conducted to evaluate the effects of covariates on PK parameters. Final model was qualified using visual predictive check (VPC), 500 data sets were simulated. The model stability was assessed by a 1000-run bootstrap analysis.
Results: PK was best described by a one CM with zero-order absorption, non-linear relative bioavailability (F1) and first-order elimination. Step-wise and non-linear effect approaches were tested to investigate the effect of dose on tolvaptan F1. A non-linear F1 significantly improved the model with a decrease in objective function value by 132 points. As dose increased from 15 mg to 120 mg, F1 decreased by 36%. Population estimates for CL/F, Vc/F, duration of absorption (D1), the amount of drug at which F1 is minimum (Vmax) and the amount of drug at which F1 is 50% (km) were: 12.6 L·h-1, 110 L, 0.589 h, 182 mg and 166 mg respectively. The inter-individual variability was 64% in CL/F, 70% in Vc/F, 238% in D1. Residual variability was described by a combined error model.
Covariate analysis revealed the following effects:
- Tolvaptan CL/F decreased with decrease in eGFR. An eGFR decrease from 69.39 (median value) to 32.47 (mL/min/1.73 m2) would result in a 33% reduction in CL/F ie, from 12.6 L/h to 8.4 L/h. Consequently, leading to higher exposures in subjects with low eGFR.
- In a previous dedicated drug-drug interaction study conducted in healthy subjects, it was observed that subjects on strong CYP3A4 inhibitor (ketoconazole 30 mg) had a 3.5- and 5.4-fold increase in Cmax and AUC∞, respectively, as compared to subjects not taking CYP3A4 inhibitor [2]. Based on the current analysis, co-administration of CYP3A4 inhibitors with tolvaptan reduced CL/F by 22%; this relatively small effect was observed as most of the patients were on weak CYP3A4 inhibitors.
- Tolvaptan CL/F decreased with increased body WT. The impact of WT on CL/F ranged from -17% (for a 42.3 kg) to +21% (for 113 kg) of the typical value.
- Tolvaptan Vc/F increased with increased body WT. The impact of WT on Vc/F ranged from -8% (for a 42.3 kg) to +8% (for a113 kg) of the typical value 110 L.
The VPC plots showed acceptable model predictive performance across all dose regimens, few peak tolvaptan plasma concentrations were outside 90% CI. Some of these observations may have been captured by the model if dosing in the fasted or fed state had been able to be incorporated as a covariate. As tolvaptan dose is increased from 30 to 90 mg, Cmax values are increased 15 to 96% when tolvaptan is dosed following a high-fat meal [3,4,5]. Dosing in the fasted or fed state was not captured in the database.
The Pop PK model developed is stable with 99.7% successful bootstrap runs.
Conclusions: Tolvaptan PK was well described by a one CM with eGFR and co-administration of CYP3A4 inhibitors as a significant covariates on CL/F.
For the treatment of ADPKD, dosing is initiated at 45 mg upon waking and prior to a meal and 15 mg about 8 hours later. Subjects should be up-titrated to 60/30 mg and 90/30 mg depending on tolerability. Increases in daily urine volume following tolvaptan are lower as eGFR decreases [6,7] despite the increases seen in tolvaptan concentrations, thus increasing subjects’ tolerability to aquaretic side effects [8]. Dose reductions to 30 mg or 15 mg once daily, depending on tolerated dose, is recommended when tolvaptan has to be administered with a potent CYP3A4 inhibitor [1].
The model is stable and acceptable, so an external validation will be performed using data from an independent trial conducted in ADPKD patients. This model will be used to obtain individual exposures for an independent study to develop a PKPD model.
References:
[1] JINARC label in EU. https://www.jinarc.eu/docs/Jinarc_SmPC_May_2015.pdf.
[2] Shoaf SE, Bricmont P, and Mallikaarjun S. Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects. Br J Clin Pharmacol 73(4):579-87, 2012.
[3] Czerwiec F. An open-label, randomized, crossover trial to assess dose strength equivalence among 30 and 90 mg strengths of oral tolvaptan tablets and to determine the effect of food (standard Food and Drug Administration high-fat breakfast) on tolvaptan pharmacokinetics following the 90-mg tablet in healthy subjects. Otsuka Clinical Study Report for Protocol 156-11-295, issued 01 May 2012.
[4] Shoaf SE, Kim SR, Bricmont P, and Mallikaarjun S. Pharmacokinetics and pharmacodynamics of single-dose oral tolvaptan in fasted and non-fasted states in healthy Caucasian and Japanese male subjects. Eur J Clin Pharmacol 68(12):1595-603, 2012.
Reference: PAGE 27 (2018) Abstr 8447 [www.page-meeting.org/?abstract=8447]
Poster: Drug/Disease Modelling - Other Topics