RESUMEN
Human radiolabeled mass balance studies are an important component of the clinical pharmacology programs supporting the development of new investigational drugs. These studies allow for understanding of the absorption, distribution, metabolism, and excretion of the parent drug and metabolite(s) in the human body. Understanding the drug's disposition as well as metabolite profiling and abundance via mass balance studies can help inform the overall drug development program. A survey of the US Food and Drug Administration (FDA)-approved new drug applications (NDAs) indicated that about 66% of the drugs had relied on findings from the mass balance studies to help understand the pharmacokinetic characteristics of the drug and to inform the overall drug development program. When such studies were not available in the original NDA, adequate justifications were routinely provided. Of the 104 mass balance studies included in this survey, most of the studies were conducted in healthy volunteers (90%) who were mostly men (>86%). The studies had at least six evaluable participants (66%) and were performed using the final route(s) of administration (98%). Eighty-five percent of the studies utilized a dose within the pharmacokinetic linearity range with 54% of the studies using a dose the same as the approved dose. Nearly all studies were performed as a single-dose (97%) study using a fit-for-purpose radiolabeled formulation. In this analysis, we summarized the current practices for conducting mass balance studies and highlighted the importance of conducting appropriately designed human radiolabeled mass balance studies and the challenges associated with inadequately designed or untimely studies.
Asunto(s)
Drogas en Investigación , Farmacología Clínica , Masculino , Estados Unidos , Humanos , Femenino , United States Food and Drug Administration , Preparaciones Farmacéuticas/metabolismo , Recolección de Datos , Aprobación de DrogasRESUMEN
On August 25, 2021, the FDA approved ivosidenib for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular isocitrate dehydrogenase 1 (IDH1) mutated cholangiocarcinoma (CCA) as detected by an FDA-approved test with disease progression after 1 to 2 prior lines of systemic therapy for advanced disease. The approval was based on data from Study AG120-C-005 (ClarIDHy), a double-blind placebo-controlled trial that randomly allocated (2:1) patients to receive either ivosidenib or placebo. Independently assessed progression-free survival (PFS) was the primary endpoint. With a median follow-up of 6.9 months, the HR for PFS was 0.37 [95% confidence interval (CI), 0.25-0.54; P < 0.0001). Overall survival (OS) was the key secondary endpoint. At the final analysis of OS, with 70.5% of patients in the placebo arm receiving ivosidenib post disease progression, a non-statistically significant improvement in the ivosidenib arm with an HR = 0.79 (95% CI, 0.56-1.12) and median OS of 10.3 months (95% CI, 7.8-12.4) and 7.5 months (95% CI, 4.8-11.1) in the ivosidenib and placebo arms, respectively, were reported. Adverse reactions occurring in >20% of patients receiving ivosidenib were fatigue/asthenia, nausea, diarrhea, abdominal pain, ascites, vomiting, cough, and decreased appetite. Adverse reactions occurring in >20% of patients receiving placebo were fatigue/asthenia, nausea, abdominal pain, and vomiting. This is the first approval for the subset of patients with CCA harboring an IDH1 mutation.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Dolor Abdominal , Adulto , Astenia , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Progresión de la Enfermedad , Método Doble Ciego , Aprobación de Drogas , Fatiga , Glicina/análogos & derivados , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Náusea , Piridinas , Estados Unidos , United States Food and Drug Administration , VómitosRESUMEN
Expedited development programs for biological products to be used in the treatment of serious conditions bring about challenges because of the compressed clinical development timeframes. As expedited development does not lessen the quality expectations, one challenge is providing adequate chemistry, manufacturing, and control (CMC) information required to support approval of a biological product. In particular, the analytical comparability and, in some cases, pharmacokinetic comparability studies needed to bridge the clinical material to the commercial material could delay submission of applications for life-saving medicines. While there is the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Topic Q5E guidance on assessing comparability of biological products before and after manufacturing changes, specific guidance on the emerging issue of conducting comparability exercises in the face of expedited drug development is lacking. In July 2019, clinical pharmacologists and product quality chemists from the US FDA and industry representatives convened an FDA workshop for a scientific exchange about considerations and challenges around conducting comparability exercises for expedited programs for biological products. This article highlights discussions from the workshop.
Asunto(s)
Productos Biológicos/farmacocinética , Productos Biológicos/normas , Desarrollo de Medicamentos/normas , Congresos como Asunto , Aprobación de Drogas , Industria Farmacéutica , Humanos , Control de Calidad , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Drug solubility, effective permeability, and intestinal metabolism and transport are parameters that govern intestinal bioavailability and oral absorption. However, excipients may affect the systemic bioavailability of a drug by altering these parameters. Thus, parameter sensitivity analyses using physiologically based pharmacokinetic (PBPK) models were performed to examine the potential impact of excipients on oral drug absorption of different Biopharmaceutics Classification System (BCS) class drugs. The simulation results showed that changes in solubility had minimal impact on Cmax and AUC0-t of investigated BCS class 1 and 3 drugs. Changes in passive permeability altered Cmax more than AUC0-t for BCS class 1 drugs but were variable and drug-specific across different BCS class 2 and 3 drugs. Depending on the drug compounds for BCS class 1 and 2 drugs, changes in intestinal metabolic activity altered Cmax and AUC0-t. Reducing or increasing influx and efflux transporter activity might likely affect Cmax and AUC0-t of BCS class 2 and 3 drugs, but the magnitude may be drug dependent. Changes in passive permeability and/or transporter activity for BCS class 2 and 3 drugs might also have a significant impact on fraction absorbed and systemic bioavailability while changes in intestinal metabolic activity may have an impact on gut and systemic bioavailability. Overall, we demonstrate that PBPK modeling can be used routinely to examine sensitivity of bioavailability based on physiochemical and physiological factors and subsequently assess whether biowaiver requirements need consideration of excipient effects for immediate release oral solid dosage forms.
Asunto(s)
Excipientes/química , Modelos Teóricos , Administración Oral , Área Bajo la Curva , Permeabilidad , SolubilidadRESUMEN
The transport and metabolism of baicalein (Ba) was studied in vitro and in Caco-2 cells. Protein binding of Ba with Caco-2 lysate showed that Ba was bound to two classes of sites: a higher affinity, lower capacity site (K(A1) = 27.6 +/- 4.7 microM(-1), n(1) = 10.6 +/- 0.6 nmol/mg) and lower affinity, higher capacity site (K(A2) = 0.015 +/- 0.0013 microM(-1), n(2) = 413 +/- 21 nmol/mg). Incubation studies of Ba with Caco-2 lysate showed substrate inhibition of both glucuronidation and sulfation, with K(m) values of 0.14 +/- 0.034 and 0.015 +/- 0.0053 microM, and K(I) values of 6.75 +/- 1.70 and 0.37 +/- 0.16 microM, respectively. In the Caco-2 monolayer, Ba (8-47 microM) displayed good apparent permeabilities (P(app)) across the membrane; P(app) was found to be increased with elevated loading concentration in both the absorptive and secretory directions. However, the efflux ratio was less than unity, negating the involvement of apical efflux transporters. The concentration ratios of Ba sulfate (BS) and glucuronide (BG) decreased with increased loading Ba concentration, suggesting that BS and BG are apically excreted via transporters, likely breast cancer resistance protein and multidrug resistance-associated protein 2, respectively. Data fit to the catenary model, composed of basolateral, cellular, and apical compartments, showed a low cellular unbound fraction (0.0019 +/- 0.00018), a high passive diffusion clearance (0.012 +/- 0.00029 ml/min/mg), and substrate inhibition, with sulfation being more readily saturated and inhibited than glucuronidation, as evidenced by smaller K(m) value (0.35 +/- 0.078 versus 1.95 +/- 0.57 microM) and K(I) value (0.58 +/- 0.20 versus 7.90 +/- 1.10 microM); these patterns paralleled those observed in the lysate incubation studies. The results showed that the catenary model aptly predicts substrate inhibition kinetics and offers significant and mechanistic insight into the transport and atypical metabolism of drugs in the Caco-2 monolayer.