Biotechnology Healthcare - November/December 2008 - (Page T2) FIGURE Examples of dosing patterns* Patient A Recommended starting dose (mg) 20 10 0 2 4 6 8 10 Recommended dosing frequency No dose escalation at any point in treatment of any magnitude or duration (total quantity = 60 mg) • Any dose that exceeds the lowest standard recommended dose – This definition includes a meaningful threshold by referring to the product Prescribing Information, but has the same shortcomings as the other estimates. Magnitude estimates. Three studies were reviewed that have measured the difference between the average ending dose and the initial dose of TNF inhibitors (Bullano 2006, Abarca 2004, Etemad 2005). This method discounts intervening dose increases, while it inflates the contribution of dosing changes that were noted at the end of the study, no matter how shortlived they were. Comparative estimates of dose elevation The preceding discussion becomes especially important when comparing dosing patterns among different treatments. Numerous analyses have compared dose elevations of TNF inhibitors in patients with RA (Ariza-Ariza 2007, Etemad 2005, Gu 2007). Since various methods have been used, study findings should be interpreted in the context of the conceptual framework presented in the previous section. Ariza-Ariza (2007) conducted a systematic review to assess the prevalence of dose escalation in a pooled sample of 8,510 patients who were treated with etanercept or infliximab; studies of adalimumab dosing patterns did not meet the inclusion criteria. The investigators estimated the percentage of treatment cases with any dose exceeding the lowest standard recommended dose (e.g., infliximab doses >3 mg/kg every 8 weeks, etanercept doses >50 mg/week). According to this definition, the prevalence of dose escalation for etanercept was 17.5 percent (95 percent confidence interval [CI], 16 percent - 19 percent), and 53.7 percent for infliximab (95 percent CI, 51.88 percent - 54.64 percent). However, when focusing on the actual magnitude of the increase, etanercept was Patient B Recommended starting dose (mg) 20 10 0 2 4 6 8 10 Recommended dosing frequency Dose at the inception of treatment is elevated at twice the recommended starting dose and remains stable thereafter, with no dose escalation (total quantity = 120 mg) Patient C Recommended starting dose (mg) 20 10 0 2 4 6 8 10 Recommended dosing frequency Dose at week 4 is increased by 50 percent, and this increase persists through week 10 (total quantity = 80 mg) Patient D 20 Recommended starting dose (mg) 10 0 2 4 6 8 10 Recommended dosing frequency Dose at week 4 is increased by 100 percent, and this increase persists through week 10 (total quantity = 100 mg) Patient E Recommended starting dose (mg) 20 10 0 2 4 6 8 10 Recommended dosing frequency Dose at week 2 is increased by 100 percent, then reverts to initial dose (total quantity = 70 mg) Patient F Recommended starting dose (mg) 20 10 0 2 4 6 8 10 Recommended dosing frequency Dose at week 2 is increased by 100 percent and remains at this level throughout treatment (total quantity = 110 mg) *Dotted horizontal line represents recommended dose in mg; dotted vertical line represents recommended dosing frequency; squares represent actual doses in hypothetical patient treatment scenario. 2
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