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.