Abstract. Physiologically based pharmacokinetic (PBPK) models are composed of a series of differential equations and have been implemented in a number of commercial software packages. These models require species-specific and compound-specific input parameters and allow for the prediction of plasma and tissue concentration time profiles after intravenous and oral administration of compounds to animals and humans. PBPK models allow the early integration of a wide variety of preclinical data into a mechanistic quantitative framework. Use of PBPK models allows the experimenter to gain insights into the properties of a compound, helps to guide experimental efforts at the early stages of drug discovery, and enables the prediction of human plasma concentration time profiles with minimal (and in some cases no) animal data. In this review, the application and limitations of PBPK techniques in drug discovery are discussed. Specific reference is made to its utility (1) at the lead development stage for the prioritization of compounds for animal PK studies and (2) at the clinical candidate selection and "first in human" stages for the prediction of human PK.

The results from this evaluation demonstrate the utility of PBPK methodology for the prediction of human pharmacokinetics. This methodology can be applied at different stages to enhance the understanding of the compounds in a particular chemical series, guide experiments, aid candidate selection and inform clinical trial design.

Relebactam is a small-molecule β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30-minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 μg/mL) for all renal groups.Relebactam is a small-molecule β-lactamase inhibitor active against classes A and C β-lactamases that is being developed as a fixed-dose combination with imipenem/cilastatin (PRIMAXIN, Whitehouse Station, NJ). 1,2 Imipenem is an approved carbapenem β-lactam antibacterial agent that covers many gram-negative organisms and certain gram-positive organisms and anaerobes. 2 Cilastatin alone has no antibacterial activity, but prevents the metabolism of imipenem by renal dehydropeptidase produced in vivo.In vitro susceptibility and hollow fiber (HF) time-kill studies found that relebactam restored the activity of subinhibitory concentrations of imipenem against imipenem-resistant isolates. [3][4][5] Animal studies further confirmed the activity of relebactam, and integrated translational pharmacokinetic/ pharmacodynamic (PK/PD) modeling suggested that the combination of imipenem/relebactam would be efficacious against the majority of imipenem-resistant strains at clinically achievable doses and concentrations. 6,7 From these

Increasing prevalence of infections caused by antimicrobial‐resistant gram‐negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime‐avibactam is a novel β‐lactam β‐lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra‐abdominal infection, and complicated urinary tract infection or hospital‐acquired ventilator‐associated pneumonia (adults only in the United States) caused by susceptible gram‐negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000–500 mg by 2‐hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime‐avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime‐avibactam pediatric dosage regimens (all by 2‐hour IV infusion) of 50–12.5 mg/kg (maximum 2,000–500 mg) q8h for those ≥6 months to 18 years old, and 40–10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2.

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Mivavotinib (TAK-659), an orally administered, small-molecule, dual inhibitor of spleen tyrosine kinase and FMS-like tyrosine kinase 3 (SYK/FLT3), is under development for the treatment of patients with advanced malignancies. In this analysis, we evaluated the population pharmacokinetics (PK) of mivavotinib and its sources of variability (covariates) in adult patients with advanced solid tumors, or relapsed/refractory B-cell lymphomas or acute myeloid leukemia, using pooled data from 159 patients enrolled in 2 phase 1/2 clinical studies. A 2-compartment model with first-order linear elimination and a first-order absorption rate (and associated lag time) adequately described the PK of mivavotinib in this patient population. The population estimates of apparent clearance (CL/F) and apparent central compartment volume (V c /F) were 31.6 L/h and 893 L, respectively, resulting in a half-life of ≈20 hours. In the final model, creatinine clearance was included as a covariate of CL/F, and sex as a covariate of V c /F. Simulations showed that steady-state exposure to mivavotinib increased with decreasing renal function. Expanding eligibility by enrolling patients with moderate renal impairment in phase 1 increased the diversity of patients in early trials and allowed the model to inform dose adjustment in patients with moderate renal impairment in future trials. In addition, simulations showed median steady-state trough concentration of mivavotinib following 70 mg twice daily and 160 mg daily dosing to be commensurate with 100 ng/mL, the level leading to >90% FLT3 inhibition per ex vivo plasma immune assays and considered a potential exposure threshold required for FLT3-driven efficacy.