Purpose: OnJune 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome^positive acute lymphoblastic leukemia (Ph + ALL) with resistance or intolerance to prior therapy including imatinib.This summary reviews the database supporting this approval. Experimental Design: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph + ALL was major hematologic response. Results: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph + ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached.The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph + ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. Conclusions: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph + ALL based on the rates and durability of cytogenetic and hematologic responses.

Although without clear scientific rationale, body size-based dosing is often used for administering monoclonal antibodies (mAbs). This simulation study compared the performance of body size-based and fixed dosing in reducing pharmacokinetic (PK) and/or pharmacodynamic (PD) variability in adults for 12 mAbs with published population PK and/or PD models. At the population level, 95th percentile intervals of concentration-time profiles, distribution, and variability of exposure for 1000 subjects after both dosing approaches were examined. At the individual level, the difference between the exposures of patients with extreme body sizes from the typical exposure following both approaches was compared. The results show that the 2 dosing approaches perform similarly across the mAbs investigated with fixed dosing being better for some mAbs and body size-based dosing being better for the others. Based on this finding, we recommend using fixed dosing in first-in-human (FIH) adult studies because it offers other advantages. When sufficient data become available, a full assessment of body size effect on PK/PD should be conducted to determine the optimal dosing approach for phase 3 trials. Other factors that may affect the selection of dosing approach were also discussed. Dosing approach for mAbs in the pediatric population is out of the scope of this study.

Therapeutic proteins (TPs) may affect the disposition of drugs that are metabolized by cytochrome P450 (CYP) enzymes, as is evident from a review of data in recently published literature and approved Biologic License Applications. Many TPs belonging to the cytokine class appear to differentially affect CYP activities. Cytokine modulators may affect CYP enzyme activities by altering cytokine effects on CYP enzymes. The alteration in CYP enzyme activities seems to result from changes in transcription factor activity for CYP enzyme expression or changes in CYP enzyme stability, which have been observed during altered immunological states such as infection and inflammation. Human growth hormone also appears to differentially affect CYP activities through unknown mechanisms. Because TP-drug interaction research is an evolving area, limited information is available during drug development on TP-drug interactions mediated by CYP inhibition or induction. The authors of this review suggest that effort be made to understand TP-drug interactions for the safe and effective use of TPs in combination with small-molecule drugs.

Purpose: To describe the Food and Drug Administration review and marketing approval considerations for panitumumab (Vectibix) for the third-line treatment of patients with epidermal growth factor receptor^expressing metastatic colorectal carcinoma. Experimental Design: Food and Drug Administration reviewed a single, open-label, multicenter trial in which 463 patients with epidermal growth factor receptor^expressing metastatic colorectal cancer who had progressed on or following treatment with a regimen containing a fluoropyrimidine, oxaliplatin, and irinotecan were randomized (1:1) to receive best supportive care (BSC) with or without panitumumab (6 mg/kg every other week) administered until disease progression or intolerable toxicity. Progression and response were confirmed by an independent review committee masked to treatment assignment. At progression, patients in the BSC-alone arm were eligible to receive panitumumab. Results: Although median progression-free survival (PFS) was similar in both treatment arms (f8 weeks), the mean PFS was f50% longer among patients receiving panitumumab than among those receiving BSC alone (96 versus 60 days, respectively) and the objective response rate in patients receiving panitumumab was 8%. However, no difference in overall survival was shown between the two study arms. Conclusions: Panitumumab received accelerated approval based on improvement in PFS and an independently confirmed response rate of 8%, similar to that observed with other active agents at this advanced stage of disease. Confirmation of clinical benefit will be required for full approval. 5 This accelerated approval was based on the surrogate end point of tumor response. The clinical benefit (i.e., improved PFS or OS) of cetuximab in a study of 572 patients who had failed both irinotecan-and oxaliplatin-based chemotherapy regimens randomized (1:1) to receive best supportive care (BSC) with or without cetuximab administered as an i.v. infusion of 400 mg/m 2 on the first dose and then 250 mg/m 2 . Patients randomized to receive cetuximab showed a statistically 5

OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011. MAIN OUTCOME MEASURES Patient demographic baseline characteristics, inclusion and exclusion criteria, trial designs, efficacy end points, and pharmacokinetic profiles were analyzed and compared across drug products. RESULTS We analyzed data for sumatriptan succinate nasal spray and zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate tablets. Seven efficacy trials had a randomized, double-blinded, placebo-controlled, parallel-group trial design. In 4 trials, patients were required to have a history of migraine attacks lasting at least 4 hours. High response rates for placebo were observed in all trials, with pain relief at 2 hours ranging from 53% to 57.5%. Nonrandomization of patients with an early placebo response design was used in the rizatriptan trial in 2011. Compared with the rizatriptan trial conducted in 1999, the 2011 rizatriptan trial reduced the placebo response rate by 6% for headache freedom at the 2-hour posttreatment end point owing to study design. The pharmacokinetic profiles between adolescents and adults were statistically similar. CONCLUSIONS High placebo response rates are consistent across all trials and may represent the principal challenge in pediatric trials of drugs for abortive treatment of migraine. Enrichment with selection of subjects with long-lasting migraine attacks is not sufficient to overcome high placebo response rates. Another enrichment strategy, the nonrandomization of patients with an early placebo response, successfully reduces the high placebo response rate for rizatriptan and is a trial design that should be considered for future pediatric trials of abortive migraine therapeutics.

A recent US Food and Drug Administration (FDA) advisory committee meeting highlighted the potential of clinical pharmacology to overcome challenges in orphan drug development.

OBJECTIVES: We investigated the changes in the IL-6 and STAT3 expression levels in cachectic and noncachectic patients with gastric, lung and breast cancer and evaluated the association between IL-6 and STAT3 levels and cancer types in terms of cachexia condition. BACKGROUND: Cancer-associated cachexia, observed in nearly 50-80 % of cancer patients, has drawn attention in advanced patients. IL-6/JAK/STAT pathway plays an essential role in the progression of cancer cachexia through the regulation of the infl ammatory response. METHODS: This study consisted of 48 gastric, breast and lung cancer patients (18 cachectic and 30 noncachectic) and healthy individuals. Total RNA isolation and cDNA synthesis was performed after the collection of blood samples. IL-6 and STAT3 expression levels were analyzed by RT-PCR analysis. RESULTS: Our fi ndings demonstrated that IL-6 mRNA levels considerably increased 19.89 ± 8.25, 5.18 ± 2.81 and 15.33±9.54-fold in gastric, lung and breast cancer patients with cachexia, respectively. Additionally, a 16.67±7.13, 14.21 ± 11.72 and 8.85 ± 3.89-fold increase in the STAT3 expression level was detected in cachectic gastric, lung and breast cancer patients, respectively (p < 0.01). CONCLUSION: STAT3 may be considered as a therapeutic target for cachectic patients with gastric, lung and breast cancer. Furthermore, IL-6 mediates STAT3 activation in cachectic gastric and breast cancer patients (Tab. 5, Fig. 2, Ref. 62).

Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Based on nonclinical and clinical evidence, the pathophysiology of partial onset seizures (POS) is similar in pediatric patients ≥ 1 month of age and adults. WHAT QUESTION DID THIS STUDY ADDRESS?  This analysis addresses whether drugs indicated for the treatment of POS in adults and pediatric patients exhibit similar exposure-response relationships for efficacy. Such information can provide support for extrapolation of efficacy from adult to pediatric populations. WHAT DID THIS STUDY ADD TO OUR KNOWLEDGE? Data from eight drugs approved in adult and pediatric patients were used to demonstrate that the relationship between drug exposure and reduction in seizure frequency is similar in the two populations. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE? As a result of this work, the US Food and Drug Administration (FDA) has concluded that the efficacy of drugs approved for the treatment of POS can be extrapolated from adults to pediatric patients 1 month of age and older, thus obviating the need for a controlled efficacy trial in the pediatric population.