NOVA will also collect detailed PK/PD data, offering further information about the relationship among natalizumab dose, body weight, and alpha\4 integrin saturation and potentially providing further validation for the models described here. The implications of the data generated by the model simulations here could be particularly beneficial for patients at higher risk of PML, as a recent retrospective study showed that extended\interval dosing is associated with a lower risk of PML than every\4\week dosing. 9 In that analysis, the average dosing interval for extended\interval dosing patients was approximately every 6 weeks, and the majority of patients had received every\4\week dosing for 1 year before the beginning of extended\interval dosing. natalizumab extended\interval dosing was modeled specifically in patients switching from every\4\week dosing to extended\interval dosing. Published population pharmacokinetic/pharmacodynamic models were used to simulate the distribution of alpha\4 integrin saturations for different body weight categories and dosing intervals (every 5, 6, 7, 8, 10, or 12 weeks). Generalized estimating equations relating alpha\4 integrin saturation to probability of multiple sclerosis lesion or relapse were derived from RESTORE trial data, which included patients (n = 175) who discontinued natalizumab after being treated every 4 weeks for 1 year and had no relapses in the year before discontinuation. The model\based simulations described indicate that every\5\week or every\6\week dosing is likely to maintain the efficacy of natalizumab, particularly at body weights 80 kg, in patients who switch after a period of stability on every\4\week dosing. The Clofibric Acid efficacy of natalizumab decreases as dosing intervals and body weight increase. Partial model validation was achieved in that observed outcomes in an impartial clinical study were similar to those predicted by the models. representing the Gd+ lesion status of patient at the = ?1,, 4), Clofibric Acid the model for the probability of lesion occurrence was was the alpha\4 integrin saturation level of patient at the .0001) for the logit response. The probability of Gd+ lesion occurrence increased at alpha\4 integrin saturation levels 40% (Physique?1). To illustrate the distribution of the alpha\4 integrin saturation level predicted at 1 year for various dosing intervals and body weight categories, the mean and 95% prediction interval (confidence interval [CI]) derived from the previous PK/PD model 18 (Table S1) are plotted in Figures?1 through?3 for the every\4\week, every\6\week, and every\12\week dosing regimens and the 60\ to 79\kg and 80\ to 99\kg body weight groups. The Clofibric Acid 95%CIs usually were fully above 40% saturation Clofibric Acid for both body weight groups receiving every\4\week dosing. A small portion of the lower 95%CI for every\6\week dosing fell below 40% saturation, with a larger portion below 40% in the higher body weight group (80\99 kg). With every\12\week dosing, the 95%CIs usually were fully below 40% saturation. Open in a separate window Physique 1 Estimated probability of gadolinium\enhancing (Gd+) lesion occurrence at 48 weeks by trough alpha\4 integrin saturation level. Clofibric Acid The resulting fitted curve of the probability of Gd+ lesion occurrence with 95% confidence intervals (CIs) is usually shown. Open circles represent the observed occurrence (Y/N) of Gd+ lesions, and red X marks represent the proportion of occurrence of lesions within each 10% bin or interval of alpha\4 integrin saturation level (eg, 0%\10%, 11%\20%) plotted versus the mean saturation level with each bin. Q4W, Lox every 4 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks. Open in a separate window Physique 3 Estimated probability of relapse at 48 weeks by trough alpha\4 integrin saturation level. The resulting fitted curve of the probability of relapse occurrence with 95% confidence intervals (CIs) is usually shown. Open circles represent the observed occurrence of relapse (Y/N), and red X marks represent the proportion of occurrence within each 10% bin or interval of alpha\4 integrin saturation level (eg, 0%\10%, 11%\20%, etc) plotted versus the mean saturation level with each bin. Q4W, every 4 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks. Similarly, the estimated mean number of Gd+ lesions at 48 weeks was low, with trough alpha\4 integrin saturation level above 40%; lesion numbers rose as alpha\4 integrin saturation level fell below 40% (Physique?2). The estimates ( SE) for the model parameter were 0 = 1.22 0.36 and 1 = ?0.13 0.02 ( .0001) for the log response. Open in a separate window Physique 2 Estimated mean number of gadolinium\enhancing (Gd+) lesions at 48 weeks by trough alpha\4 integrin saturation level. The resulting fitted curve of the mean number of Gd+ lesions with 95% confidence intervals (CIs) is usually shown. Red X marks represent the mean lesion number within each 10% bin or interval of alpha\4 integrin saturation level (eg, 0%\10%, 11%\20%, etc) plotted versus the mean saturation level with each bin. Q4W, every 4 weeks; Q6W, every 6 weeks; Q12W, every 12 weeks. For the model of relapse probability, the estimates ( SE) for the model parameter were 0 = ?2.18 0.31 and 1 = ?0.02 0.01 ( .0001) for the logit response. Whereas the number and probability of Gd+ lesions increased sharply in the models, the simulated probability of relapse occurrence rose gradually with decreasing alpha\4 integrin saturation level without a notable difference in the rate of change above and below 40% saturation.