Table 4.
Parameters of the Final Samidorphan Population Pharmacokinetic Model
| Parameter (Units) | Estimate | %RSE | 95% CI | CV% |
|---|---|---|---|---|
| CL/F (L/h) | 35.4 | 1.65 | 34.3‐36.5 | … |
| Vc/F (L) | 297 | 1.63 | 288‐306 | … |
| Vp/F (L) | 124 | 8.87 | 102‐146 | … |
| Ka (h) | 6.61 | 14.2 | 4.77‐8.45 | … |
| ALAG (h) | 0.323 | 5.57 | 0.288‐0.358 | … |
| Q/F (L/h) | 12.1 | 7.89 | 10.2‐14.0 | … |
| WT on CL/F a | 0.75 (fixed) | … | … | … |
| WT on Vc/F a | 1.0 (fixed) | … | … | … |
| Rifampin inducer effect (in the presence vs absence of rifampin) on CL/F | 2.70 | 3.06 | 2.54‐2.86 | … |
| Moderate hepatic impairment (moderate hepatic impairment vs normal hepatic function) on CL/F | 0.810 | 9.04 | 0.667‐0.953 | … |
| Severe renal impairment (severe renal impairment vs normal renal function) on CL/F | 0.570 | 5.96 | 0.503‐0.637 | … |
| Food (fed vs fasted) on Ka | 0.107 | 36.9 | 0.0296‐0.184 | … |
| Change in ALAG b , c | 10.1 | 11.0 | 7.92‐12.3 | … |
| Formulation (samidorphan tablet vs OLZ/SAM bilayer tablet) on ALAG | 1.41 | 5.80 | 1.25‐1.57 | … |
| Interindividual variability | ||||
| CL/F | 0.087 | 11.9 | 0.066‐0.107 | 29.4 |
| Vc/F | 0.054 | 19.0 | 0.034‐0.075 | 23.3 |
| Ka | 1.76 | 16.8 | 1.18‐2.34 | 219 |
| ALAG | 0.131 | 24.8 | 0.067‐0.195 | 36.2 |
| Vp/F | 0.681 | 24.5 | 0.354‐1.010 | 98.8 |
| Q/F | 0.223 fixed | … | … | 50.0 |
| Residual variability in σ2 prop | 0.061 | 6.87 | 0.053‐0.069 | 24.7 |
σ2, variance of residual error quantity ε; ALAG, absorption lag time; CI, confidence interval; CL/F, apparent clearance; CV, coefficient of variation; F, bioavailability; IIV, interindividual variability; Ka, rate of absorption; OLZ/SAM, combination of olanzapine and samidorphan; Q/F, intercompartmental clearance; RSE, relative standard error; Vc/F, apparent volume of central compartment; Vp/F, apparent volume of peripheral compartment; WT, time‐changing body weight.
Fixed at allometric exponent.
Fixed at estimate from previous stable model where effect was reliably estimated.
Dose time was not recorded in ALK3831‐A305, so imputed dose timing was used. Consequently, the change in ALAG for this study in comparison to population ALAG was estimated. ALK3831‐A305 had a 4‐week treatment period, and participants received oral study drug once daily. Pharmacokinetic samples were taken before dosing on the first day of treatment and subsequently during weeks 2 and 4 of the treatment period.
Where estimate >0.15, CV calculated as rather than square root of .