Doses Evaluated in Clinical Pharmacology Studies Investigating the Effect of Intrinsic and Extrinsic Factors on PK and Safety: Case Examples from Approved Drug Development Programs.

Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.

Model-based simulation to support the approval of isatuximab alone or with dexamethasone for the treatment of relapsed/refractory multiple myeloma in Japanese patients.

This study aimed to support dosing regimen selection for isatuximab as a single agent or in combination with dexamethasone for Japanese patients with relapsed/refractory multiple myeloma (RRMM). A joint model characterizing the dynamics of serum M-protein kinetics and its association with progression-free survival (PFS) was developed using data from 201 evaluable Japanese and non-Japanese patients with RRMM enrolled in two monotherapy phase I/II trials, where Japanese patients (n = 31) received isatuximab at 10 or 20 mg/kg once weekly (qw) for 4 weeks then every 2 weeks (q2w) in subsequent cycles (10 or 20 mg/kg qw-q2w). Among non-Japanese patients, 38 received isatuximab 20 mg/kg qw-q2w in combination with dexamethasone.

Improved Prediction of the Drug-Drug Interactions of Pemafibrate Caused by Cyclosporine A and Rifampicin via PBPK Modeling: Consideration of the Albumin-Mediated Hepatic Uptake of Pemafibrate and Inhibition Constants With Preincubation Against OATP1B.

Pemafibrate (PMF) is highly albumin-bound (>99.8%) and a substrate for hepatic uptake transporters (OATP1B) and CYP enzymes. Here, we developed a PBPK model of PMF to capture drug-drug interactions (DDI) incurred by cyclosporine (CsA) and rifampicin (RIF), the two OATP1B inhibitors.

Preincubation-dependent and long-lasting inhibition of organic anion transporting polypeptide (OATP) and its impact on drug-drug interactions.

Preincubation with cyclosporin A (CsA), a potent inhibitor of organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3, enhanced its inhibitory effects on these transporters in vitro. A similar effect was observed upon preincubation with some other inhibitors. Removing these from the incubation media did not readily reverse the inhibition on OATP1B1 and OATP1B3.

Increase in the systemic exposure of primary metabolites of Midazolam in rat arising from CYP inhibition or hepatic dysfunction.

The main purpose of this study is to demonstrate the possibility of increase in the systemic exposure of drug metabolites by CYP-inhibition or acute hepatitis. Midazolam (MDZ) was used as a model substrate of CYP3A and 1-aminobenzotriazole (ABT) was used as a CYP-inhibitor. After oral pretreatment with ABT, MDZ was intravenously injected to rats and the plasma profiles of MDZ and its primary metabolites, 1'-hydroxy MDZ and 4-hydroxy MDZ, were observed.

Pharmacokinetic Herb-Drug Interactions: Insight into Mechanisms and Consequences.

Herbal medicines are currently in high demand, and their popularity is steadily increasing. Because of their perceived effectiveness, fewer side effects and relatively low cost, they are being used for the management of numerous medical conditions. However, they are capable of affecting the pharmacokinetics and pharmacodynamics of coadministered conventional drugs.

Population pharmacokinetics of cefditoren pivoxil in non-infected adults.

Population pharmacokinetic analysis was conducted on cefditoren pivoxil (CDTR-PI), a third generation oral antibiotic to evaluate the effect of covariates on pharmacokinetic parameters. Plasma concentrations of cefditoren (CDTR, total number of sampling points: 2864) obtained from healthy adult subjects, elderlies, and subjects with renal dysfunction (287 subjects) after CDTR-PI administration as well as demographic data of those subjects were used for analysis. We conducted the population pharmacokinetic analysis of CDTR-PI using a nonlinear mixed effects modeling (NONMEM) method.

The role of cyclophilin D in interspecies differences in susceptibility to hepatotoxic drug-induced mitochondrial injury.

Test compound A ((5Z)-6-[(2R,3S)-3-({[(4-Chloro-2-methylphenyl)sulfonyl]amino}methyl) bicyclo[2.2.2]oct-2-yl]hex-5-enoic acid) was withdrawn from premarketing clinical trials due to severe liver injury.

Disruption of ZO-1/claudin-4 interaction in relation to inflammatory responses in methotrexate-induced intestinal mucositis.

Purpose: Methotrexate (MTX)-induced intestinal mucositis limits the use of the drug. We previously reported that MTX-dependent production of reactive oxygen species is an initiating signal leading to neutrophil migration and intestinal barrier dysfunction. Moreover, alterations of zonula occludens (ZO)-1, an integral component of tight junctions (TJs), contribute to its dysfunction.

The mechanism of the down-regulation of hepatic transporters in rats with indomethacin-induced intestinal injury.

Background: Previously, we reported that hepatic transporters were down-regulated consistent with intestinal injury in indomethacin (IDM)-treated rats.

Aim: The purpose of this study was to characterize this mechanism of the down-regulation of hepatic transporters in IDM-treated rats.

Methods: Hepatic nuclear receptor expressions, oxidative stress condition and the expression of hepatic transporters were evaluated in rats with IDM-induced intestinal injury with or without the administration of mucosal protectant ornoprostil, a prostaglandin E1 analogue, or aminoguanidine (AG), an iNOS inhibitor.

Long-lasting inhibitory effects of saquinavir and ritonavir on OATP1B1-mediated uptake.

Previously, we reported a long-lasting inhibition of transport mediated by organic anion-transporting polypeptides (OATPs) in humans and rats by cyclosporin A (CsA). In the present study, we examined the effects of several other compounds on OATP1B1-mediated transport, with a focus on long-lasting inhibition. Effects of coincubation, preincubation, or preincubation plus coincubation of 12 compounds on uptake of estrone 3-sulfate (E1 S) in OATP1B1-expressing HEK293T cells were examined.

CYP3A5 gene variation influences cyclosporine A metabolite formation and renal cyclosporine disposition.

Background: Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend on the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intrarenal CsA accumulation.

Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria.

Phenformin causes lactic acidosis in clinical situations due to inhibition of mitochondrial respiratory chain complex I. It is reportedly taken up by hepatocytes and exhibits mitochondrial toxicity in the liver. In this study, uptake of phenformin and [(14)C]tetraethylammonium (TEA) and complex I inhibition by phenformin were examined in isolated liver and heart mitochondria.

Clinical significance of organic anion transporting polypeptides (OATPs) in drug disposition: their roles in hepatic clearance and intestinal absorption.

Organic anion transporting polypeptide (OATP) family transporters accept a number of drugs and are increasingly being recognized as important factors in governing drug and metabolite pharmacokinetics. OATP1B1 and OATP1B3 play an important role in hepatic drug uptake while OATP2B1 and OATP1A2 might be key players in intestinal absorption and transport across blood-brain barrier of drugs, respectively. To understand the importance of OATPs in the hepatic clearance of drugs, the rate-determining process for elimination should be considered; for some drugs, hepatic uptake clearance rather than metabolic intrinsic clearance is the more important determinant of hepatic clearances.

P-glycoprotein mediated efflux in Caco-2 cell monolayers: the influence of herbals on digoxin transport.

Ethnopharmacological Relevance: Several herbal medicines are concomitantly used with conventional medicines with a resultant increase in the recognition of herb-drug interactions. The phytomedicines Vernonia amygdalina Delile (VA), family Asteraceae; Azadiractha indica A. Juss (NL), family Meliaceae; Morinda lucida Benth (MLB), family Rubiaceae; Cymbopogon citratus Stapf (LG), family Poaceae; Curcuma longa L.

Potential P-glycoprotein-mediated drug-drug interactions of antimalarial agents in Caco-2 cells.

Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells.

Long-lasting inhibition of the intestinal absorption of fexofenadine by cyclosporin A in rats.

The purpose of the present study is to examine the long-lasting inhibition of intestinal organic anion transporting polypeptides (Oatps) by cyclosporin A (CsA) in rats using fexofenadine (FEX) as a probe drug. We examined the pharmacokinetics of FEX after its intravenous or oral administration to rats at 3 or 24 h after the oral administration of CsA. When FEX was administered at 3 h after the administration of CsA, its plasma concentration increased regardless of whether it was administered intravenously or orally.

Long-lasting inhibitory effects of cyclosporin A, but not tacrolimus, on OATP1B1- and OATP1B3-mediated uptake.

Cyclosporin A (CsA) causes a number of clinically relevant drug-drug interactions (DDIs) by inhibiting OATP1B1 and OATP1B3. In the present study, long-lasting inhibitory effects of CsA on these transporters were examined in comparison to tacrolimus (TCR). OATP1B1- and OATP1B3-expressing HEK293T cells, OATP1B1-expressing MDCK II cells, and human hepatocytes were preincubated with CsA or TCR, and uptake studies were carried out in their presence or absence.

Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women.

Purpose: Letrozole is an orally active aromatase inhibitor for the treatment of breast cancer. The objectives of this study were to examine the pharmacokinetic profile of letrozole in Japanese subjects and to identify factors that influence variability in the pharmacokinetics of letrozole using population pharmacokinetic (PPK) analysis.

Methods: Twenty-five healthy postmenopausal Japanese women were enrolled in the study and received 2.

Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions.

OATP1B1 and OATP1B3 are transporters that are expressed on the sinusoidal membrane of hepatocytes; they accept a number of therapeutic reagents as their substrates. In vitro and in vivo studies have shown that some drugs inhibit these transporters and cause clinically relevant drug-drug interactions (DDIs). Among these drugs, cyclosporin A markedly increases the plasma concentrations of OATP1B1 substrates.

Multiple mechanisms underlying troglitazone-induced mitochondrial permeability transition.

Troglitazone, a thiazolidinedione class antidiabetic drug, was withdrawn from the market because of its severe idiosyncratic hepatotoxicity. It causes a mitochondrial permeability transition (MPT), which may in part contribute to its hepatotoxicity. In the present study, the mechanism of troglitazone mitochondrial toxicity was investigated in isolated rat liver mitochondria.

Zonula Occludens-1 alterations and enhanced intestinal permeability in methotrexate-treated rats.

Purpose: The molecular mechanisms that underlie the methotrexate (MTX)-mediated disruption of intestinal barrier function have not been fully characterized. Epithelial barrier function is determined in large part by a multiprotein complex located at the most apical part of the lateral membrane, which is referred to as a tight junction (TJ). In the present study, we examined the alteration of zonula occludens-1 (ZO-1), which is a scaffolding protein that plays a pivotal role in the formation of TJs, to identify an additional molecular mechanism for epithelial barrier dysfunction.

Long-lasting inhibition of the transporter-mediated hepatic uptake of sulfobromophthalein by cyclosporin a in rats.

Cyclosporin A (CsA) is a well known inhibitor of the organic anion-transporting polypeptide (OATP/Oatp) family transporters, causing a large number of transporter-mediated drug-drug interactions in clinical situations. In the present study, we examined the inhibitory effect of CsA on the hepatic uptake of sulfobromophthalein (BSP) in rats, focusing on a long-lasting inhibition. Twenty-one hours after the subcutaneous administration of CsA, the hepatic clearance of BSP was decreased.

Physiologically based pharmacokinetic modeling to predict transporter-mediated clearance and distribution of pravastatin in humans.

Hepatobiliary excretion mediated by transporters, organic anion-transporting polypeptide (OATP) 1B1 and multidrug resistance-associated protein (MRP) 2, is the major elimination pathway of an HMG-CoA reductase inhibitor, pravastatin. The present study examined the effects of changes in the transporter activities on the systemic and liver exposure of pravastatin using a physiologically based pharmacokinetic model. Scaling factors, determined by comparing in vivo and in vitro parameters of pravastatin in rats for the hepatic uptake and canalicular efflux, were obtained.

The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling.

Purpose: The objective is to confirm if the prediction of the drug-drug interaction using a physiologically based pharmacokinetic (PBPK) model is more accurate. In vivo Ki values were estimated using PBPK model to confirm whether in vitro Ki values are suitable.

Method: The plasma concentration-time profiles for the substrate with coadministration of an inhibitor were collected from the literature and were fitted to the PBPK model to estimate the in vivo Ki values.