The aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.
Individual concentration-time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post-dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme-linked immunosorbent assay.
A two compartment model with parallel linear and non-linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V1 ), peripheral volume (V2 ), inter-compartmental clearance, maximum elimination capacity (VM) and concentration at half-maximum elimination capacity were 0.135 l day(-1) , 2.71 l, 1.98 l, 0.371 l day(-1) , 8.03 μg day(-1) and 27.7 ng ml(-1) , respectively. Inter-individual variability (IIV) was included on CL, V1 , V2 and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V1 and V2 significantly reduced IIV.
The small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.