Evaluation of omadacycline dosing regimens in Chinese using population pharmacokinetic-pharmacodynamic analysis.

PURPOSE: Omadacycline (PTK-0796) is a first-in-class aminomethylcycline for adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible pathogens. We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of omadacycline, considering the impact of covariates, particularly ethnicity, on PK and determined the PK/PD cutoff values for dosing regimens. METHODS: Utilizing nonlinear mixed-effects modeling, we pooled data from 11 clinical trials for PopPK analysis. The first-order conditional estimation with interaction (FOCEI) method in NONMEM facilitated model parameter estimation. Employing a stepwise model selection strategy, with forward addition (P < 0.01) and backward deletion (P < 0.001), we assessed the potential impacts of covariates on omadacycline PK, including baseline age, body weight, sex, race, body mass index, body surface area, baseline albumin, creatine clearance, and formulation. After validating the model through various methods, the final PopPK model underwent Monte Carlo simulations to generate the PK profile for the Chinese population. This enabled AUC calculation and assessment of the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for various dosing regimens and bacterial strains. RESULTS: Omadacycline's PK can be adequately characterized by a three-compartment model. Body weight, sex, race, and drug formulation statistically influenced its PK. Asians and non-Asians exhibit similar exposure after intravenous infusion, but oral dosing results in much higher exposures than in non-Asians. Monte Carlo simulation indicates that IV-only or IV/PO sequential therapy regimens provide adequate attainment for all major pathogens causing ABSSSI and CABP. PK/PD cutoffs were generally above the MIC90 value of recent clinical isolates from China. CONCLUSIONS: In conclusion, the approved regimen for China achieved adequate target attainment for all pathogens typically associated with these infections. The higher oral exposure observed in Asians may enhance efficacy without affecting safety or tolerability.

Ethnic sensitivity assessment of the antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer.

PURPOSE: Trastuzumab emtansine (T-DM1) is indicated for previously treated HER2-positive metastatic breast cancer. Ethnic sensitivity assessment of T-DM1 was conducted using data from eight clinical studies to ensure that the clinically recommended dose is appropriate across ethnicities. METHODS: Four approaches were used: (1) non-compartmental analysis (NCA) comparing pharmacokinetic parameters of T-DM1 and relevant analytes across ethnic groups, (2) population pharmacokinetic (popPK) analysis assessing the impact of ethnicity on pharmacokinetics, (3) comparison of T-DM1 pharmacokinetics in Japanese patients versus the global population, and (4) exposure-response analyses assessing the impact of ethnicity on safety and efficacy. RESULTS: NCA pharmacokinetic parameters (T-DM1, total trastuzumab, DM1) were comparable across ethnic groups; mean cycle 1 T-DM1 AUCinf was 475, 442, and 518 day µg/mL for white (n = 461), Asian (n = 68), and others (n = 57), respectively. PopPK analysis showed that ethnicity (white, Asian, and others) was not a significant covariate for T-DM1 pharmacokinetics (n = 671). Additionally, visual predictive check plots indicated that observed pharmacokinetic profiles in Japanese patients (n = 42) were within the prediction interval generated from the final PopPK model. Exposure-response analyses showed that ethnicity was not a significant covariate impacting efficacy or hepatotoxicity risk, but there was a trend of greater thrombocytopenia risk among Asians versus non-Asians, which could not be explained by similar exposure between the ethnic groups. Most Asians with thrombocytopenia were able to continue T-DM1 using dose-adjustment rules recommended for the global population. CONCLUSIONS: These results suggest that T-DM1 pharmacokinetics are comparable across ethnic groups and that use of the current dosing regimen is appropriate across ethnicities.