Pharmacometrics-Based Considerations for the Design of a Pharmacogenomic Clinical Trial Assessing Irinotecan Safety

Abstract

Purpose: Pharmacometric models provide useful tools to aid the rational design of clinical trials. This study evaluates study design-, drug-, and patient-related features as well as analysis methods for their influence on the power to demonstrate a benefit of pharmacogenomics (PGx)-based dosing regarding myelotoxicity.

Methods: Two pharmacokinetic and one myelosuppression model were assembled to predict concentrations of irinotecan and its metabolite SN-38 given different UGT1A1 genotypes (poor metabolizers: CL_SN-38: -36%) and neutropenia following conventional versus PGx-based dosing (350 versus 245 mg/m² (-30%)). Study power was assessed given diverse scenarios (n = 50-400 patients/arm, parallel/crossover, varying magnitude of CL_SN-38, exposure-response relationship, inter-individual variability) and using model-based data analysis versus conventional statistical testing.

Results: The magnitude of CL_SN-38 reduction in poor metabolizers and the myelosuppressive potency of SN-38 markedly influenced the power to show a difference in grade 4 neutropenia (<0.5·10⁹ cells/L) after PGx-based versus standard dosing. To achieve >80% power with traditional statistical analysis (χ²/McNemar's test, α = 0.05), 220/100 patients per treatment arm/sequence (parallel/crossover study) were required. The model-based analysis resulted in considerably smaller total sample sizes (n = 100/15 given parallel/crossover design) to obtain the same statistical power.

Conclusions: The presented findings may help to avoid unfeasible trials and to rationalize the design of pharmacogenetic studies.

Keywords: UGT1A1; irinotecan model; neutropenia; pharmacogenomics; study design.

Fig. 1

Integrated PK/PD model linking irinotecan dosing to neutropenia as an important adverse drug reaction. CPT-11: irinotecan; SN-38: 7-ethyl-10-hydroxycamptothecin; SN-38G: SN-38 glucuronide. UGT: uridine diphosphate glucuronosyl-transferase; CL: clearance; Q: intercompartmental CL; k: rate constants; SN-38 and SN-38G were assumed to be formed from CPT-11 and SN-38 according to first-order processes. The semi-mechanistic model of myelosuppression allowed to describes the time course of neutrophils: it consists of a proliferating compartment (Prol) representing stem and progenitor cells sensitive to the myelosuppressive agent, a compartment of circulating neutrophils in blood (Circ; Circ₀: baseline value), and a maturation chain with three transit compartments (T1-T3), enabling the prediction of a time delay between drug administration and the observed myelosuppressive effect. γ: feedback parameter, accounting for the impact of endogenous growth factors on the proliferation rate; k_prol: proliferation rate constant determining the rate of cell division.

Fig. 2

Workflow of the study design evaluation. Upper panel: The study population of poor metabolizers was randomized into two treatment arms (parallel study design) or two treatment sequences (crossover study design). A 3-period/2-sequence/2-treatment crossover design was chosen to ensure that the dose preceding the assessment of grade 4 neutropenia was the same for both treatment sequences. *For clinical study design evaluations, an alternative study design with PGx-based dosing instead of standard dosing as the second study period was additionally investigated. Red bars mark study periods for which myelosuppression was determined in the standard statistical analysis. Middle panel: 500 studies were simulated given a specific study design and scenario. Lower panel: Workflow of (A) standard statistical analysis and (B) pharmacometric model-based analysis to determine a potential difference in neutropenia after standard versus PGx-based dosing. STD: standard; PGx: pharmacogenomics-based; G4N: grade 4 neutropenia.

Fig. 3

Time course of neutrophil concentrations in patients with genotype *1/*1 (wild-type, left panel) or *28/*28 and *1/*28 (“poor metabolizers”, middle and right panel). For wild-type UGT1A1, a standard dose of irinotecan (350 mg/m²) was simulated. For poor metabolizers, myelosuppression after a standard dose (350 mg/m², middle panel) versus an individualized PGx-based dose (245 mg/m², right panel) is shown. The presented exemplary stochastic simulations were based on 200 patients and considered inter-individual pharmacokinetic and pharmacodynamic variability in myelosuppression. The nadir occurs at different time points. The dashed horizontal line indicates grade 4 neutropenia (0.5·10⁹ cells/L).

Fig. 4

Impact of different study designs and varied sample sizes on study power. Left panel: parallel design; right panel: crossover design (see Fig. 2).

Fig. 5

Power of different study designs given a) varied doses of irinotecan (standard dose/PGx-adjusted dose for poor metabolizers), b) perturbed values of the parameter slope, c) varied magnitudes of the parameter CL_{SN-38_PM} (PGx effect, expressed as fraction of CL_{SN-38_WT} = 1040 L/h) and d) different unexplained inter-individual variability associated with slope and CL_{SN-38_PM}. Scenarios depicted in the plots were based on a parallel design with sample size n = 200/study arm. In Fig. 5a, filled circles represent irinotecan regimens with 30% difference between standard and PGx-based doses and empty circles depict lower irinotecan doses as used in combination chemotherapy regimens as well as dose reductions of −50% and − 25% as recommended for poor metabolizers. CL_{SN-38_WT}: clearance of SN-38 in patients with wild-type UGT1A1*1/*1 genotype; CL_{SN-38_PM}: clearance of SN-38 in poor metabolizers with respect to UGT1A1 (patients with *28/*28 or *1/*28 genotype); IIV: inter-individual variability; %CV: coefficient of variation.

Fig. 6

Full power versus sample size curves using parametric power estimation (PPE) based on SSE (stochastic simulation and estimation) for different study scenarios. Left panel: Parallel study design (see default study scenario); right panel: crossover study design (see alternative study scenario). The green shaded area indicates the uncertainty in the power estimate due to Monte-Carlo noise (n = 500). Power curves are shown for sample sizes corresponding to 50–99% power.