Population pharmacokinetics–pharmacodynamics of alemtuzumab (Campath^®) in patients with chronic lymphocytic leukaemia and its link to treatment response

Abstract

AimsTo characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). MethodsNonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response. ResultsAlemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where Vmax (mg h -1 ) was [1020 ¥ (WBC count/10 ¥ 10 9 l -1 ) 0.194 ], Km was 338 mg l -1 , V1 was 11.3 l, Q was 1.05 l h -1 and V2 was 41.5 l. Intersubject variability (ISV) in Vmax, Km, V1 and V2 was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for Emax, 306 mg l -1 for EC50, 1.56 ¥ 10 9 cells l -1 h -1 for Kin and 0.029 per h for Kout. The probability of achieving a complete or partial response was Ն50% when the maximal trough concentration exceeded 13.2 mg ml -1 or when AUC0-t exceeded 484 mg h -1 ml -1 . ConclusionsAlemtuzumab displayed time-and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response.

Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

“…Rarely does a combined linear and non-linear process describe the elimination of antibodies (Kuester et al, 2008). Values of the final parameters were similar to those reported for other antibodies, with regard to CL from the central compartment and Q, V1 and V2 (Kovarik et al, 2001;Bruno et al, 2005;Ng et al, 2006;Dartois et al, 2007;Mould et al, 2007;Kuester et al, 2008;Lu et al, 2008). This indicates that the HuHMFG1 antibody, similar to other therapeutic antibodies, is mainly distributed in the serum.…”

“…Indeed, a structural two-compartmental model is commonly reported to describe the behaviour of antibodies. In these models, the associated elimination is mainly linear (Kovarik et al, 2001;Bruno et al, 2005;Ng et al, 2006;Dartois et al, 2007) and less frequently non-linear (Mould et al, 1999(Mould et al, , 2007. Rarely does a combined linear and non-linear process describe the elimination of antibodies (Kuester et al, 2008).…”

Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study

“…Using an improved pharmacokinetics model to achieve adequate but not excessive drug exposure should optimise alemtuzumab therapy (and probably that of other MoAbs). 16,17 On the basis of the classic schedule, patients undergoing intravenous alemtuzumab therapy receive a theoretical total of 1080 mg, divided into individual doses of 30 mg each.…”

Population Pharmacokinetics of Therapeutic Monoclonal Antibodies: Examples and Estimation Method Performance Differences

“…Estimates for the volume of the central (V 1 ) and peripheral (V 2 ) compartments were quite similar for the different mAbs with the exception of alemtuzumab. Compared to other mAbs, alemtuzumab not only had a much larger V 1 and V 2 (11.3 L and 41.5 L, respectively), but between-subject variability in both of these parameters was also larger (84 %CV and 179 %CV, respectively) (23). It is uncertain as to why these population parameter estimates for alemtuzumab are in stark contrast to what was observed for many of the other therapeutic mAbs.…”

“…Similarly, a population PK/PD analysis in patients with B-cell chronic lymphocytic leukemia found that alemtuzumab exhibited nonlinear clearance attributable to saturation of target-mediated clearance mechanisms (23). The only covariate found to influence the PK of alemtuzumab was white blood cell (WBC) count, which was a strong positive predictor of V max .…”