Diane R. Mould's scientific contributions

To characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). Nonlinear 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. Alemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where V(max) (microg h(-1)) was [1020 x (WBC count/10 x 10(9) l(-1))(0.194)], K(m) was 338 microg l(-1), V(1) was 11.3 l, Q was 1.05 l h(-1) and V(2) was 41.5 l. Intersubject variability (ISV) in V(max), K(m), V(1) and V(2) 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 E(max), 306 microg l(-1) for EC(50), 1.56 x 10(9) cells l(-1) h(-1) for K(in) and 0.029 per h for K(out). The probability of achieving a complete or partial response was >/=50% when the maximal trough concentration exceeded 13.2 microg ml(-1) or when AUC(0-tau) exceeded 484 microg h(-1) ml(-1). Alemtuzumab 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.

Alemtuzumab (Campath®, MabCampath®) is a humanized IgG monoclonal antibody targeting the CD52 antigen and is approved for treatment of B-cell chronic lymphocytic leukemia (B-CLL) following treatment with alkylating agents and failing fludarabine treatment. Nonlinear mixed effects modeling was used to characterize the population pharmacokinetics in patients with NHL and CLL after both single dose and multiple dose treatment regimens (n = 118). Model building followed standard procedures. First, an appropriate structural model was identified. Covariate screening was undertaken using generalized additive models to identify those patient characteristics that influenced alemtuzumab pharmacokinetics. Covariates deemed important were then tested using a forward stepwise approach. Only those covariates deemed statistically significant at the 0.05 level were retained in the model. Once the final forward model was identified, the model was reduced using more stringent criteria to remain in the model (P <0.001). The final model was validated using an independent data set after data-splitting (80:20, n = 32). A secondary analysis was also performed using noncompartmental analysis of pharmacokinetic data obtained from only B-CLL patients (n = 16). A 2-compartment model with Michaelis-Menten elimination best characterized alemtuzumab pharmacokinetics. White blood cell (WBC) count significantly influenced the maximal rate of elimination (Vmax) in a linear manner, while body weight affected Vmax based on a power function. Central volume of distribution was proportional to patient weight, estimated at 7.6 L for a 70 kg patient. Distribution volume at steady-state (Vdss) was 0.18 L/kg. Vdss in B-CLL patients ranged from 0.09 to 0.40 L/kg (median, 0.15 L/kg). The Michaelis constant was estimated at 6.1 mg/mL. Due to nonlinear elimination kinetics, no single estimate for half-life can be reported. For a typical 70-kg patient with elevated WBC of 100 × 109 cells/L, receiving a first dose of 3 mg, the model-predicted half-life was ~8 hours. After a log-decline in WBC to 1.0 × 109 cells/L, the half-life increased to ~50 hours, and a further log-decline in WBCs to 0.1 × 109 cells/L, after 5 doses, resulted in a half-life of ~9 days (214 hours). In B-CLL patients (n = 8), individual observed half-life values after the first 30 mg dose ranged from 2 to 32 hours (median, 8.3 hours) and after the last 30 mg dose (n = 16) ranged from 1 to 14 days (median, ~6 days). Model validation resulted in comparable results, thus indicating the model parameters were consistent across data sets. In summary, alemtuzumab pharmacokinetics were weight-dependent, concentration-dependent, and WBC-dependent. As the number of CD52 expressing cells is depleted, which is reflected in a decrease of WBC and lymphocyte counts, alemtuzumab half-life increases. Also, as alemtuzumab concentrations increase, the maximal rate of elimination further decreases thereby increasing alemtuzumab’s half-life to a value of ~6 days.