Table 2.
Population PK parameter estimates and bootstrap analysis results for the final model
| Final model | Bootstrap b | ||||
|---|---|---|---|---|---|
| Parameter a | Estimate | RSE (%) | 2.5th percentile | Median | 97.5th percentile |
| KA, h−1 | 0.9 | 8.9 | 0.6 | 0.9 | 1.1 |
| CL/F, L/h | 90 | 7.4 | 71.6 | 88.0 | 107.7 |
| Vc/F, L | 24 | 33.3 | 1.2 | 16.8 | 72.6 |
| Q/F, L/h | 111 | 12.1 | 71.1 | 105.3 | 147.7 |
| Vp/F, L | 669 | 17.6 | 425.0 | 623.4 | 902.2 |
| CLm/F3ACDAP , L/h | 20.5 | 6 | 17.8 | 20.5 | 23.3 |
| Vm/F3ACDAP , L | 36 | 10.7 | 28.3 | 36.9 | 52.3 |
| Exponent for SCR on CLm/F3ACDAP c | 0.7 | 31.8 | 0.3 | 0.7 | 1.1 |
| Between subject variability (%CV) | |||||
| KA, % | 36.2 | 47.3 | 8.2 | 35.6 | 70.3 |
| CL/F, % | 48.1 | 28.9 | 33.5 | 47.6 | 61.6 |
| Vc/F, % | 182.4 | 36 | 100.7 | 208.5 | 401.1 |
| Q/F, % | 48.7 | 44.3 | 25.6 | 49.6 | 79.1 |
| Vp/F, % | 89.8 | 41.8 | 44.7 | 80.7 | 119.9 |
| CLm/F3ACDAP, % | 38.6 | 21.3 | 27.7 | 37.3 | 44.8 |
| CL/F‐Vc/F covariance d | 0.5 | 42.4 | −0.4 | 0.6 | 1.4 |
| Residual error | |||||
| 3,4‐DAP proportional error, % | 34.8 | 16.7 | 29.2 | 34.3 | 42.1 |
| 3‐Ac DAP proportional error, % | 20.1 | 12.7 | 17.8 | 19.9 | 23.3 |
3‐Ac DAP, 3‐N‐acetyl‐3,4‐diaminopyridine; 3,4‐DAP, 3,4‐diaminopyridine; CL/F, CLm/F3ACDAP , and Q/F, apparent oral clearance (L/h) for parent, metabolite, and intercompartment clearance (L/h), respectively; CV, coefficient of variation; F3ACDAP is the product of Fm and F; Fm, fraction of 3,4‐DAP converted to its metabolite (3‐Ac DAP); KA, absorption rate; RSE, relative standard error; SCR, serum creatinine; Vc/F, Vp/F and Vm/F3ACDAP, volume of distribution (L) for central compartment, parent, and metabolite respectively.
aPopulation estimates for CL/F, V/F, and CLm/F3ACDAP were scaled using the median weight of 82 kg: CL (L/h)=90*(WT/82)0.75;Vp/F(L)=669*(WT/82); CLm/F3ACDAP (L/h)=20.5*(WT/82)0.75*(0.8/SCR)0.7. WT is the body weight. bA nonparametric bootstrap analysis of the final model was performed with 500 replicates. cThe following mathematical relationship describes the exponent for SCR on CLm/F3ACDAP: CLm/F3ACDAP (L/h)=20.5*(WT/82)0.75*(0.8/SCR)0.7, where 0.8 is the median serum creatinine in mg/dL. dCorrelation coefficient for CL and Vc between subject variability parameters: 0.53.