RESUMO
A recent US Food and Drug Administration (FDA) advisory committee meeting highlighted the potential of clinical pharmacology to overcome challenges in orphan drug development.
Assuntos
Descoberta de Drogas/tendências , Produção de Droga sem Interesse Comercial , Farmacologia Clínica/tendências , Animais , Descoberta de Drogas/legislação & jurisprudência , Humanos , Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Farmacologia Clínica/legislação & jurisprudência , Doenças Raras/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência , United States Food and Drug Administration/tendênciasRESUMO
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.
Assuntos
Sistema Enzimático do Citocromo P-450/fisiologia , Legislação de Medicamentos/tendências , Preparações Farmacêuticas/metabolismo , Proteínas/farmacocinética , Proteínas/uso terapêutico , Animais , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/farmacocinética , Interações Medicamentosas/fisiologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Legislação de Medicamentos/normas , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Preparações Farmacêuticas/normas , Proteínas/normas , Estados UnidosRESUMO
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.
