Yumi Cleary

Clinical Drug–Drug Interactions Through Cytochrome P450 3A (CYP3A) for the Selective ALK Inhibitor Alectinib

The efficacy and safety of alectinib, a central nervous system–active and selective anaplastic lymphoma kinase (ALK) inhibitor, has been demonstrated in patients with ALK‐positive (ALK+) non–small cell lung cancer (NSCLC) progressing on crizotinib. Alectinib is mainly metabolized by cytochrome P450 3A (CYP3A) to a major similarly active metabolite, M4. Alectinib and M4 show evidence of weak time‐dependent inhibition and small induction of CYP3A in vitro. We present results from 3 fixed‐sequence studies evaluating drug–drug interactions for alectinib through CYP3A. Studies NP28990 and NP29042 enrolled 17 and 24 healthy subjects, respectively, and investigated potent CYP3A inhibition with posaconazole and potent CYP3A induction through rifampin, respectively, on the single oral dose pharmacokinetics (PK) of alectinib. A substudy of the global phase 2 NP28673 study enrolled 15 patients with ALK+ NSCLC to determine the effect of multiple doses of alectinib on the single oral dose PK of midazolam, a sensitive substrate of CYP3A. Potent CYP3A inhibition or induction resulted in only minor effects on the combined exposure of alectinib and M4. Multiple doses of alectinib did not influence midazolam exposure. These results suggest that dose adjustments may not be needed when alectinib is coadministered with CYP3A inhibitors or inducers or for coadministered CYP3A substrates.

Evaluating a physiologically based pharmacokinetic model for prediction of omeprazole clearance and assessing ethnic sensitivity in CYP2C19 metabolic pathway

PurposeThe purpose of this study is to evaluate the ethnicity-specific population models in the SimCYP Simulator® for prediction of omeprazole clearance with attention to differences in the CYP2C19 metabolic pathway.MethodsThe SimCYP® models incorporating Caucasian, Chinese, and Japanese population-specific demographic, physiological, and enzyme data were applied to simulate omeprazole pharmacokinetics. Published pharmacokinetic data of omeprazole after intravenous or oral administration in Caucasian, Chinese, and Japanese were used for the evaluation.ResultsFollowing oral administration, the ratio of the predicted to observed geometric mean of omeprazole clearance in Caucasian extensive metabolizers (EMs) was 0.88. The ratios in Chinese EMs were 1.16 and 0.99 after intravenous and oral administration, respectively. The ratios in Japanese EMs were 0.88 and 0.71 after intravenous and oral administration, respectively.Significant differences (2-fold) in the observed oral clearance of omeprazole were identified between Caucasian and Asian (Chinese and Japanese) EMs while the observed oral and intravenous clearances of omeprazole were similar between Chinese and Japanese EMs. Physiologically based pharmacokinetics (PBPK) models within SimCYP accurately predicted the difference in the observed oral clearance between Caucasian and Chinese EMs but overpredicted the difference between Caucasians and Japanese EMs due to under-prediction of oral clearance in Japanese EMs.ConclusionsThe PBPK model within SimCYP adequately predicted omeprazole clearance in Caucasian, Chinese, and Japanese EMs and the 2-fold differences in clearance of omeprazole between Caucasian and Asian EMs. This may lead to early identification of ethnic sensitivity in clearance and the need for different dosing regimens in a specific ethnic group for substrates of CYP2C19 which can support the rational design of bridging clinical trials.

Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.

Analysis of “On/Off” Kinetics of a CETP Inhibitor Using a Mechanistic Model of Lipoprotein Metabolism and Kinetics

RG7232 is a potent inhibitor of cholesteryl‐ester transfer protein (CETP). Daily oral administration of RG7232 produces a dose‐ and time‐dependent increase in high‐density lipoprotein‐cholesterol (HDL‐C) and apolipoproteinA‐I (ApoA‐I) levels and a corresponding decrease in low‐density lipoprotein‐cholesterol (LDL‐C) and apolipoproteinB (ApoB) levels. Due to its short plasma half‐life (∼3 hours), RG7232 transiently inhibits CETP activity during each dosing interval (“on/off” kinetics), as reflected by the temporal effects on HDL‐C and LDL‐C. The influence of RG7232 on lipid‐poor ApoA‐I (i.e., pre‐β1) levels and reverse cholesterol transport rates is unclear. To investigate this, a published model of lipoprotein metabolism and kinetics was combined with a pharmacokinetic model of RG7232. After calibration and validation of the combined model, the effect of RG7232 on pre‐β1 levels was simulated. A dose‐dependent oscillation of pre‐β1, driven by the “on/off” kinetics of RG7232 was observed. The possible implications of these findings are discussed.

Low Potential of Basimglurant to Be Involved in Drug-Drug Interactions: Influence of Non-Michaelis-Menten P450 Kinetics on Fraction Metabolized

Basimglurant, a novel mGlu5-negative allosteric modulator under development for the treatment of major depressive disorder, is cleared via cytochrome P450 (P450)-mediated oxidative metabolism. Initial enzyme phenotyping studies indicated that CYP3A4/5 dominates basimglurant metabolism and highlights a risk for drug-drug interactions when it is comedicated with strong CYP3A4/5 inhibitors or inactivators; however, a clinical drug-drug interaction (DDI) study using the potent and selective CYP3A4/5 inhibitor ketoconazole resulted in an area under the curve (AUC) AUCi/AUC ratio of only 1.24. A further study using the CYP3A4 inducer carbamazepine resulted in an AUCi/AUC ratio of 0.69. More detailed in vitro enzyme phenotyping and kinetics studies showed that, at the low concentrations attained clinically, basimglurant metabolic clearance is catalyzed mainly by CYP1A2. The relative contributions of the enzymes were estimated as 70:30 CYP1A2:CYP3A4/5. Using this information, a clinical study using the CYP1A2 inhibitor fluvoxamine was performed, resulting in an AUCi/AUC ratio of 1.60, confirming the role of CYP1A2 and indicating a balanced DDI risk profile. Basimglurant metabolism kinetics show enzyme dependency: CYP1A2-mediated metabolism follows Michaelis-Menten kinetics, whereas CYP3A4 and CYP3A5 follow sigmoidal kinetics [with similar constant (KM) and S50 values]. The interplay of the different enzyme kinetics leads to changing fractional enzyme contributions to metabolism with substrate concentration, even though none of the metabolic enzymes is saturated. This example demonstrates the relevance of non–Michaelis-Menten P450 enzyme kinetics and highlights the need for a thorough understanding of metabolism enzymology to make accurate predictions for human metabolism in vivo.

Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib

Alectinib is approved and recommended as the preferred first‐line treatment for patients with anaplastic lymphoma kinase (ALK)‐positive non–small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open‐label study (NCT02621047) investigated a single 300‐mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child‐Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration–time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7‐196) and 176% (90%CI 98.4‐315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic‐impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.

Model‐Based Assessments of CYP‐Mediated Drug–Drug Interaction Risk of Alectinib: Physiologically Based Pharmacokinetic Modeling Supported Clinical Development

Alectinib is a selective anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK‐positive non‐small cell lung cancer. Alectinib and its major active metabolite M4 exhibited drug–drug interaction (DDI) potential through cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C8 in vitro. Clinical relevance of the DDI risk was investigated as part of a rapid development program to fulfill the breakthrough therapy designation. Therefore, a strategy with a combination of physiologically based pharmacokinetic (PBPK) modeling and limited clinical trials focused on generating informative data for modeling was made to ensure extrapolation ability of DDI risk. The PBPK modeling has provided mechanistic insight into the low victim DDI risk of alectinib through CYP3A4 by a novel two‐dimensional analysis for fmCYP3A4 and FG, and demonstrated negligible CYPs 2C8 and 3A4 enzyme‐modulating effects at clinically relevant exposure. This work supports that alectinib can be prescribed without dose adjustment for CYP‐mediated DDI liabilities.

Development of a PBPK Model for Mefloquine and its Application alongside a Clinical Effectiveness Model to Select an Optimal Dose for Prevention of Malaria in Young Caucasian Children

To predict the optimal chemoprophylactic dose of mefloquine in infants of 5–10 kg using physiologically based pharmacokinetic (PBPK) and clinical effectiveness models.

A Phase 1 healthy male volunteer single escalating dose study of the pharmacokinetics and pharmacodynamics of risdiplam (RG7916, RO7034067), a SMN2 splicing modifier: Risdiplam healthy volunteer Phase 1

Risdiplam (RG7916, RO7034067) is an orally administered, centrally and peripherally distributed, survival of motor neuron 2 (SMN2) mRNA splicing modifier for the treatment of spinal muscular atrophy (SMA). The objectives of this entry‐into‐human study were to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of risdiplam, and the effect of the strong CYP3A inhibitor itraconazole on the PK of risdiplam in healthy male volunteers.