Population of Pharmacokinetics of Tanezumab in Pateints with Chronic Low Back Pain

Aims: Tanezumab is a monoclonal lgG antibody targeted against nerve growth factor (NGF). It is currently under clinical development for the treatment of chronic pain associated with osteoarthritis (OA), cancer and chronic low back pain (CLBP). A population pharmacokinetic (PK) analysis was conducted using pooled data from three CLBP studies. The purposes of this analysis were to i) characterize the PK of tanezumab after intravenous (IV) and subcutaneous (SC) administrations; ii) identify the factors that may impact the PK; iii) predict exposures for the PK/Pharmacodynamic (PKPD) analyses.

Methods: One Phase 2a study and one Phase 2b study with a long term open label extension were included in the analysis. In the former study, patients were treated with 1 dose of 200 mg/kg IV.  In the latter study, 2 doses of either 5mg, 10mg or 20mg IV, 8 weeks apart, were administered, followed by entry into the long term safety extension study with up to 3 q8W IV doses, followed by up to 4 q8W SC doses, of either 10mg or 20mg. Plasma tanezumab concentrations over time were analyzed using nonlinear mixed effects modeling approach (NONMEM version 7.2). The estimation method was the first order conditional with interaction (FOCEI). Based on past experience [1,2] the potential covariates of interest were Dose, Age, SEX, baseline body weight (BWT), baseline creatinine clearance (BCRCL), and baseline albumin (BALB) on clearance (CL) and BWT and SEX on volume of distribution.

Results: In total 5332 observations from 1158 patients (536 males and 622 females) were included in the analysis, in which 17% of the patients followed SC dosing. The PK of tanezumab was best characterized by a two-compartment model with parallel linear and nonlinear elimination pathways with a first order absorption (Ka) after SC administration.  Body weight was considered to be a structual covariate on CL, central volume (V1) and peripheral volume (V2). The other covariates identified were Dose, SEX, BCRCL and BALB on CL, and SEX on V1. The parameter estimates for a typical female subject (BWT of 84.81 kg, BCRCL of 102.9 ml/min, BALB of 4.4 g/mL) receiving a 5mg IV dose were 0.133 L/day, 2.3 L, 2.07 L, 6.05 mg/day, and 22.6 mg/L for CL, V1, V2, maximum elimination capacity (Vm) and concentration at half of Vm (Km), respectively.  The absolute bioaviability (F) for SC and Ka were estimated to be 0.76 and 0.245 day-1.  Interindividual varibility (IIV expressed as %CV) on linear CL, V1 and V2, and Vm were estimated with a correlation between CL and V1. BWT was the most influential covariate reducing IIV in CL from 29% to 23% and other covariates effects only accounted for ~ 2% reduction of IIV in CL. IIVs for CL, V1, V2 and Vm were 21%, 19%, 27% and 66%, respectively. Patients were assigned to one of two additive residual error terms using a previously described mixture model [1]. The probability of patients being assigned to the lower residual error term was estimated to be 84.3%. The impact of covariates on the parameters are presented in Table 1.

Table 1. The impact of covariates on the parameters

 

Covariate relationship

Parameter estimates (RSE%)

Impact

WT on CL

0.611 (7.61)

A 10% change in body weight leads a 6% change in CL

BCCL on CL

0.139 (20.65)

A 10% change in CRCL leads a 1% change in CL

Dose_10mg on CL

-0.0856 (9.91)

CL is 8.6% lower at dose of 10mg compared to 5mg

SEX on CL (male)

0.118 (16.1)

Males have a 11.8% higher CL than females

BALB on CL

-0.373 (25.09)

A 10% change in baseline albumin leads to a 4% change in CL

WT on V1

0.417 (11.08)

A 10% change in body weight leads a 4% change in V1

SEX on V1 (male)

0.164 (13.66)

Males have 16.4% higher V1 than females

WT on V2

0.374 (23.16)

A 10% change in body weight leads a 4% change in V2

 

Conclusion: The parameter estimates and identified covariates describing the disposition of tanezumab are similar to a previous population PK analysis in an OA population, where the fast nonlinear pathway was considered to be related to target mediated clearance [1]. The rate and extent of absorption following SC administration was also characterized.  The identified statistically significant covariates are not considered clinically relevant.

References:

1.      Jonsson E.N. et al. Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoathritis pain. Br J Clin Pharmacol. 2016 April; 81(4):688-699.

2.      Ordas I, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. CPT 2012 Feb 22.