This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.
The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 Ci) of [ 3 H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n ؍ 6) and plasma was collected over 26 weeks in study B (n ؍ 7). Supportive data were obtained from a single-dose [ 3 H]caspofungin tissue distribution study in rats (n ؍ 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t 1/2 ؍ 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at ϳ92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.Caspofungin (CANCIDAS; MK-0991) is a parenteral antifungal agent that inhibits 1,3--D-glucan synthesis, which forms a critical component of many fungal cell walls (4). Caspofungin is active against many clinically important fungal species, including Candida spp. and Aspergillus spp. (3,5,7,14), and in clinical trials it has been shown to be efficacious in the treatment of esophageal candidiasis (1, 15, 16), invasive candidiasis (9), and invasive aspergillosis (J. Maertens, I. Raad, G. Petrikkos, et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-868, 2002). This paper describes results from two studies conducted in healthy human subjects to investigate the disposition of caspofungin following intravenous (i.v.) infusion of radiolabeled caspofungin and supportive studies of [ 3 H]caspofungin tissue distribution in rats, in vitro metabolism, and in vitro binding and partitioning in human plasma and blood. The metabolites of caspofungin, a cyclic hexapeptide, in humans have been previously reported (2). Caspofungin is the major component of radioactivity in plasma and urine in the first 24 to 30 h postdose, with a ring-opened form of caspofungin, M0, comprising a minor component. At time points of Ն5 days, M0 was the major component in plasma, and urine radioactivity was largely comprised of the synthetic amino acid dihydoxyhomotyrosine (M1) and its N-acetyl derivative (M2). Caspofungin...
In-vitro studies were conducted to assess the impact of CYP2C9 genotype on the metabolism (methyl hydroxylation) and pharmacokinetics of celecoxib, a novel cyclooxygenase-2 inhibitor and CYP2C9 substrate. When compared to cDNA-expressed wild-type CYP2C9 (CYP2C9*1), the Vmax/Km ratio for celecoxib methyl hydroxylation was reduced by 34% and 90% in the presence of recombinant CYP2C9*2 and CYP2C9*3, respectively. These data indicated that the amino acid substitution at position 359 (Ile to Leu) elicited a more pronounced effect on the metabolism of celecoxib than did a substitution at position 144 (Arg to Cys). The Vmax/Km ratio was also decreased in microsomes of livers genotyped CYP2C9*1/*2 (47% decrease, mean of two livers), or CYP2C9*1/*3 (59% decrease, one liver). In all cases, these changes were largely reflective of a decrease in Vmax, with a minimal change in Km. Based on simulations of the in-vitro data obtained with the recombinant CYP2C9 proteins, it was anticipated that the pharmacokinetics of celecoxib (as a much as a five-fold increase in plasma AUC) would be altered (versus CYP2C9*1/*1 subjects) in subjects genotyped heterozygous or homozygous for the CYP2C9*2 (Cys144) or CYP2C9*3 (Leu359) allele. In a subsequent clinical study, the AUC of celecoxib was increased (versus CYP2C9*1/*1 subjects) approximately 2.2-fold (range, 1.6-3-fold) in two CYP2C9*1/*3 subjects and one CYP2C9*3/*3 subject receiving a single oral dose (200 mg) of the drug. In contrast, there was no significant change in celecoxib AUC in two subjects genotyped CYP2C9*1/*2.
ABSTRACT:Caspofungin (CANCIDAS, a registered trademark of Merck & Co., Inc.) is a novel echinocandin antifungal agent used in the treatment of esophageal and invasive candidiases, invasive aspergillosis, and neutropenia. Available data suggest that the liver is a key organ responsible for caspofungin elimination in rodents and humans. Caspofungin is primarily eliminated by metabolic transformation; however, the rate of metabolism is slow. Accordingly, it was hypothesized that drug uptake transporters expressed on the basolateral domain of hepatocytes could significantly influence the extent of caspofungin uptake and subsequent elimination. In this study, experiments ranging from perfused rat livers to heterologous expression of individual hepatic uptake transporters were utilized to identify the transporter(s) responsible for the observed liver-specific uptake of this compound. Data from perfused rat liver studies were consistent with the presence of carrier-mediated caspofungin hepatic uptake, although this process appeared to be slow. To identify a relevant hepatic uptake transporter, we developed novel Tet-on HeLa cells expressing OATP1B1 (OATP-C, SLC21A6) and OATP1B3 (OATP8, SLC21A8), whose target gene can be overexpressed by the addition of doxycycline. A modest but statistically significant uptake of caspofungin was observed in cells overexpressing OATP1B1, but not OATP1B3. Taken together, these findings suggest that OATP1B1-mediated hepatic uptake may contribute to the overall elimination of this drug from the body.
Wnt/LRP5 signaling is a central regulatory component of bone formative and resorptive activities, and the pathway inhibitor DKK1 is a suppressor of bone formation and bone mass accrual in mice. In addition, augmented DKK1 levels are associated with high bone turnover in diverse low bone mass states in rodent models and disease etiologies in human. However, examination of the precise role of DKK1 in the normal skeleton and in higher species requires the development of refined DKK1-specific pharmacological tools. Here, we report the strategy resulting in isolation of a panel of fully human anti-DKK1 antibodies applicable to studies interrogating the roles of mouse, rhesus, and human DKK1. Selected anti-DKK1 antibodies bind primate and human DKK-1 with picomolar affinities yet do not appreciably bind to DKK2 or DKK4. Epitopes mapped within the DKK1 C-terminal domain necessary for interaction with LRP5/6 and consequently effectively neutralized DKK1 function in vitro. When introduced into naïve normal growing female mice, IgGs significantly improved trabecular bone volume and structure and increased both trabecular and cortical bone mineral densities in a dose-related fashion. Furthermore, fully human DKK1-IgG displayed favorable pharmacokinetic parameters in non-human primates. In summary, we demonstrate here a rate-limiting function of physiologic DKK1 levels in the regulation of bone mass in intact female mice, amendable to specific pharmacologic neutralization by newly identified DKK1-IgGs. Importantly the fully human IgGs display a profile of attributes that recommends their testing in higher species and their use in evaluating DKK1 function in relevant disease models.The Wnt signaling pathway plays a key role in embryonic differentiation, adult tissue maintenance, stem cell biology, oncogenesis, and the etiology of degenerative diseases and has been directly linked to regulation of bone metabolism (1-5). Loss of function mutations in the Wnt coreceptor LRP5 results in osteoporosis-pseudoglioma syndrome in humans and mice characterized by low bone mass with reduced bone formation (6). Consistently, allelic LRP5 variants have been associated with altered bone mineral densities (BMD) 3 and fracture risk in human populations (7). Importantly, discrete LRP5 gain-of-function mutations lead to a high bone mass (HBM) phenotype in humans and mice (8 -11). Interestingly, HBM LRP5 mutations have been shown to be refractory to the inhibitory effects of Dickkopf-1 (DKK1) on canonical Wnt-signaling (9, 12), thus, strongly suggesting that the impairment of DKK1 signaling plays a role in the etiology of the HBM phenotype (9, 12). Recently this mechanism has been expanded to include other inhibitors of Wnt signaling such as sclerostin (13). Analyses of genetically DKK1 insufficient mice provides compelling evidence for an inhibitory role of DKK1 on new bone formation and a titratable effect on bone mass accrual resulting in a HBM phenotype that is maintained throughout adulthood (14, 15). DKK1 is a high affinity ligand for LRP...
Vorinostat's favorable clinical pharmacology and drug interaction profile aid in the ease of administration of vorinostat for the treatment of advanced CTCL and will be beneficial in continued assessment for other oncologic indications. Although a number of studies have been conducted to elucidate the detailed pharmacokinetic profile of vorinostat, more rigorous assessment of vorinostat pharmacokinetics, including clinical drug interaction studies, will be informative.
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