Population pharmacokinetics of tanezumab following intravenous or subcutaneous administration to patients with osteoarthritis or chronic low back pain.

AIMS: Describe population pharmacokinetics of intravenous (IV) and subcutaneous (SC) tanezumab across Phase 2b/3 studies of osteoarthritis and chronic low back pain. METHODS: Data from 10 studies of IV or SC tanezumab (2.5-20 mg every 8 wk for up to 56 wk) were included in a multistep analysis. In Step 1, a 2-compartment model with linear and nonlinear elimination (based on prior analysis of pre-2015 IV osteoarthritis studies) was expanded to include other pre-2015 studies. In Step 2, post-2015 SC studies were combined into the model. Steps 3 and 4 evaluated impact of baseline nerve growth factor (NGF) and treatment-emergent anti-drug antibodies (TE ADA). RESULTS: SC bioavailability was estimated at 62-76%. The key disposition parameters CL, Vc , Vp and KM were estimated to be 0.133 L d-1 , 2.6 L, 1.77 L and 31.2 µg L-1 , respectively. Plasma tanezumab concentration was predicted to reach Cmax at 8.9-11.2 days following single and multiple SC administration in typical patients within the dose range of SC Phase 3 studies (2.5-10 mg every 8 wk). Exposure of a typical patient was similar between IV and SC for the second part of the dosing interval (wk 4-8). Covariates selected on the absorption parameters were weight, age, sex and injection site. Baseline NGF had minimal effect on maximum elimination capacity and TE ADA status was associated with slightly higher tanezumab clearance (6-7%). CONCLUSION: Our model adequately described plasma tanezumab concentration vs. time following IV or SC administration. Weight was the most influential covariate with respect to absorption of tanezumab in comparison to patient population (osteoarthritis and chronic low back pain) or other demographics. There was no clinically relevant effect of baseline NGF or TE ADA on tanezumab PK.

Prediction of relative change in free nerve growth factor following subcutaneous administration of tanezumab, a novel monoclonal antibody to nerve growth factor.

Tanezumab is a monoclonal antibody against nerve growth factor (NGF). We investigated tanezumab pharmacokinetic (PK)-NGF relationships and predicted the extent of systemic free NGF suppression with target-mediated drug disposition (TMDD) modeling using data from three pivotal phase III interventional studies (NCT02697773, NCT02709486, and NCT02528188) in patients with osteoarthritis. Patients received tanezumab 2.5 mg or 5 mg every 8 weeks (q8w) subcutaneously. A TMDD model using a previously established population PK model was used to describe plasma tanezumab and serum total NGF concentration data, and simulations were performed to predict "unobserved" free NGF versus time profiles and dose-response relationships for free NGF. A total of 2992 patients had available data for plasma tanezumab or serum total NGF concentrations and were included in the analysis; 706 of these had data for both tanezumab and total NGF concentrations. The model generally performed well to predict observed total NGF concentrations up to ~24 weeks after each dose. Simulations suggested free NGF concentration would be suppressed by ~75% (median) near the peak of tanezumab concentration and by less than 5% (median) around the trough tanezumab concentration with a tanezumab 2.5 mg q8w regimen. Free NGF concentration was predicted to return to baseline level at ~8 weeks (95% prediction interval: 5-16 weeks) after the last tanezumab dose. This model adequately described plasma tanezumab and serum total NGF concentrations following s.c. administration of tanezumab 2.5 or 5 mg q8w, allowed prediction of relative change in systemic free NGF following s.c. administration of tanezumab.

Criteria to Reevaluate Anti-drug Antibody Assay Cut Point Suitability in the Target Population.

After tier 1 and 2 cut points for anti-drug antibody (ADA) assays are derived during pre-study assay validation in a population, there is a need to verify the continued appropriateness of the previously derived cut points during sample analysis in the same or different populations, per FDA guidance (US HHS, FDA, CDER, CBER, 2019). Proper sample size-dependent criteria with statistical underpinning were derived and presented in this technical note to aid in assessing the appropriateness of tier 1 and tier 2 cut points, respectively.

Anti-drug Antibody Assay Validation: Improved Reporting of the Assay Selectivity via Simpler Positive Control Recovery Data Analysis.

Anti-drug antibody (ADA) assay selectivity is evaluated during assay validation to assess the potential for individual matrices to interfere with detection of ADA. While current EMA and FDA guideline documents suggest comparative analysis with and without matrix, they do not provide specific recommendations on the acceptance criteria such as an acceptable percent positive control (PC) recovery range or positive rate. Industry has adopted an approach where recovery of PC spiked sample is expected to fall within ± 20% (80 to 120%) vs. that for the PC material spiked in negative control matrix or assay buffer. Here, it is proposed that ADA assay selectivity evaluated using a qualitative assessment of PC recovery vs. a PK-like quantitative method may be more appropriate. The PC recovery test should focus on the reliability of the method to detect the low PC level in individual samples and avoid false-negative ADA reporting. Therefore, it is proposed that assessment of high PC level as well as the assessment of quantitative percent recovery (within ± 20%) should not be included in the test. The recovery test may be viewed as acceptable should a pre-selected number of individual samples (for example at least 8 or 9 out of 10) prepared at the low PC concentration of the assay score as ADA positive.

A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01).

BACKGROUND: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US. METHODS: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios for PK parameters, Cmax, AUCT, and AUCinf, were within the 80.00-125.00% pre-specified equivalence window. RESULTS: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration-time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for Cmax, AUCT, and AUCinf were within 80.00-125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups. CONCLUSIONS: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles. TRIAL REGISTRATION: CT.gov identifier NCT01844804.

Evaluation of the human serum albumin column as a discovery screening tool for plasma protein binding.

A total of 69 compounds with a variety of chemical structures were assayed using a human serum albumin column in combination with UV and mass spectrometric detection. A moderate correlation, R(2)=0.661, between the plasma protein binding, determined by traditional techniques of equilibrium dialysis or ultrafiltration, and chromatographic retention factor (k'/k'+1) was observed. Disparity between the regression line and numerous samples was observed across the entire range of plasma protein binding. Attempts to discriminate between compounds from the data set to achieve better correlation based physico-chemical properties were unsuccessful. Good agreement was observed for retention times obtained with UV detection with mobile phase containing phosphate buffer and mass spectrometric detection with mobile phase containing acetate buffer. Essentially identical data were obtained for compounds analyzed in singlet or cassette for minimally or highly bound (>90% bound) compounds. Analysis of cassettes containing compounds with plasma protein binding greater than 90% did not cause column overload, even at analyte concentrations up to 100 microg/ml. Diverse results were obtained when chromatographic retention was used to rank order various classes of compounds. Better correlation with ordering from known binding was obtained when a compound class contained a wide range of protein binding, in contrast to when compounds within a given class were all highly bound.