Pharmacokinetic/Pharmacodynamic Model of CW002, an Investigational Intermediate Neuromuscular Blocking Agent, in Healthy Volunteers.

BACKGROUND: CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency. METHODS: Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose-response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored. RESULTS: A four-compartment model was fit to the concentration-time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose. CONCLUSIONS: CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.

Transporter-Mediated Alterations in Patients With NASH Increase Systemic and Hepatic Exposure to an OATP and MRP2 Substrate.

The expression of hepatic transporters, including organic anion transporting polypeptides (OATPs) and multidrug resistance-associated proteins (MRPs), is altered in nonalcoholic steatohepatitis (NASH); however, functional data in humans are lacking. In this study, 99m Tc-mebrofenin (MEB) was used to evaluate OATP1B1/1B3 and MRP2 function in NASH patients. Healthy subjects (n = 14) and NASH patients (n = 7) were administered MEB (∼2.5 mCi). A population pharmacokinetic model was developed to describe systemic and hepatic MEB disposition. Study subjects were genotyped for SLCO1B1 variants. NASH increased systemic and hepatic exposure (median ± 2 SE, healthy vs. NASH) to MEB (AUC0-300,blood : 1,780 ± 242 vs. 2,440 ± 775 µCi*min/L, P = 0.006; AUC0-180,liver : 277 ± 36.9 vs. 433 ± 40.3 kcounts*min/sec, P < 0.0001) due to decreased biliary clearance (0.035 ± 0.008 vs. 0.017 ± 0.002 L/min, P = 0.0005) and decreased Vcentral (11.1 ± 0.57 vs. 6.32 ± 1.02 L, P < 0.0001). MEB hepatic CLuptake was reduced in NASH and also in healthy subjects with SLCO1B1 *15/*15 and *1A/*15 genotypes. The pharmacokinetics of drugs that are OATP1B1/1B3 and MRP2 substrates may be substantially altered in NASH.