Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial.

Purpose: We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist (RA), a 5-hydroxytryptamine-3 (5-HT) RA, and dexamethasone for preventing chemotherapy-induced nausea and vomiting in patients receiving carboplatin-containing chemotherapy.

Patients And Methods: Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT RA, and dexamethasone. The primary end point was the complete response (CR; no vomiting and no rescue therapy) rate in the overall phase (0-120 hours).

Investigation of the boxed warnings in package inserts of prescription medicines for medical professionals in Japan.

Objective: In the Japanese Pharmacists Act, article 25-2, revised in 2013, it states that pharmacists shall provide the necessary information and guidance to the patient based on pharmaceutical knowledge and experience for ensuring the proper use of the medicine dispensed. The package insert is one of the documents to be referred to when providing the information and guidance. The boxed warnings in package inserts that include the precautions and responses are the most significant parts, however, the suitability of boxed warnings for pharmaceutical practice has not been evaluated.

Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients.

Purpose: The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients.

Methods: Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.

Simultaneous determination of itraconazole and its CYP3A4-mediated metabolites including -desalkyl itraconazole in human plasma using liquid chromatography-tandem mass spectrometry and its clinical application.

Background: Itraconazole (ITZ), a triazole antifungal agent, is metabolized to hydroxy-ITZ (OH-ITZ), keto-ITZ (KT-ITZ), and -desalkyl ITZ (ND-ITZ) by cytochrome P450 3A4. The pharmacokinetics of ND-ITZ remain largely unknown due to the lack of an accurate and reliable determination method. This study aimed to develop a simultaneous determination method for ITZ and its three major metabolites including ND-ITZ in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and then apply the method in a clinical setting.

Impact of flavin-containing monooxygenase 3 and CYP2C19 genotypes on plasma disposition and adverse effects of voriconazole administered orally in immunocompromised patients.

Flavin-containing monooxygenase (FMO) 3 together with cytochrome P450 (CYP) 2C19 play a significant role in voriconazole N-oxidation. This study aimed to evaluate the influence of FMO3 and CYP2C19 genotypes on the plasma disposition and adverse effects of voriconazole in immunocompromised patients. Sixty-five Japanese immunocompromised patients receiving oral voriconazole were enrolled.

Validated determination method of tramadol and its desmethylates in human plasma using an isocratic LC-MS/MS and its clinical application to patients with cancer pain or non-cancer pain.

Background: This study aimed to develop a simultaneous determination method for tramadol and its desmethylates in human plasma using isocratic liquid chromatography coupled to tandem mass spectrometry and to validate it for pharmacokinetic evaluation in patients with cancer pain or non-cancer pain.

Methods: The pretreatments for human plasma involved protein precipitation using acetonitrile and methanol under basic conditions. Tramadol, -desmethylate, -desmethylate, and -didesmethylate were separated on an octadecylsilyl column filled with 3-μm particles using isocratic mixture of methanol and 0.

Mycophenolic acid exposure and complement fraction C3 influence inosine 5'-monophosphate dehydrogenase activity in systemic lupus erythematosus.

Background Mycophenolate mofetil has recently been reported to be effective against systemic lupus erythematosus. The influence of the pharmacokinetics of mycophenolic acid, the active form of mycophenolate mofetil and the major inactive mycophenolic acid phenolic glucuronide on the activity of the target enzyme inosine 5'-monophosphate dehydrogenase, is expected to be revealed. The aim of this study was to identify the factors associated with inosine 5'-monophosphate dehydrogenase activity in systemic lupus erythematosus patients.

Saturated Metabolism of Voriconazole N-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses.

Metabolic saturation of voriconazole based on the trough plasma concentrations of voriconazole and its major metabolite N-oxide were evaluated according to CYP2C19 genotypes in 58 Japanese patients receiving voriconazole (median dose; 200 mg twice daily) for prophylaxis or treatment. Predose trough plasma concentrations of voriconazole and N-oxide were monitored on day 5 d or later after initiation of voriconazole treatment. Large interindividual variations in trough plasma concentrations of voriconazole and N-oxide were observed.

[Optimization of Immunosuppression and the Prevention of Fungal Infection in Autoimmune Diseases].

Mycophenolate mofetil (MMF) has recently been reported to be effective in the treatment of systemic lupus erythematosus (SLE). The therapeutic range of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG), and factors affecting their pharmacokinetics, remain to be clarified. The influence of the pharmacokinetics of MPA and MPAG on the activity of inosine 5'-monophosphate dehydrogenase (IMPDH), a target of the MPA, also remains to be revealed.

ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affect renal function in patients with rheumatoid arthritis.

Background: This study aimed to evaluate the blood exposure of and clinical responses to tacrolimus based on genetic variants of CYP3A5 and ABCB1 in patients with rheumatoid arthritis.

Methods: Seventy rheumatoid arthritis patients treated with oral tacrolimus once daily were enrolled. Blood concentrations of tacrolimus and its major metabolite 13-O-demethylate at 12h after dosing were determined.

Impact of inflammation and concomitant glucocorticoid administration on plasma concentration of triazole antifungals in immunocompromised patients.

Background: The expression of hepatic CYP3A decreases with inflammatory response but increases with glucocorticoid administration. The aim of this study was to evaluate the plasma concentration of voriconazole and itraconazole under inflammatory conditions and glucocorticoid therapy.

Methods: Forty-one voriconazole- and 42 itraconazole-treated immunocompromised patients were enrolled in this study.

Blood distribution of bortezomib and its kinetics in multiple myeloma patients.

Objectives: Pharmacokinetic disposition of bortezomib in the blood has not been fully characterized in humans. This study aimed to evaluate the blood distribution of bortezomib and its kinetics in multiple myeloma patients.

Design And Method: Eighteen multiple myeloma patients receiving bortezomib-dexamethasone combination therapy were enrolled.

Interindividual variations in aprepitant plasma pharmacokinetics in cancer patients receiving cisplatin-based chemotherapy for the first time.

The pharmacokinetics of aprepitant, a neurokinin-1 receptor antagonist, have not been fully evaluated in clinical settings. The aim of this study was to characterize the plasma pharmacokinetics of aprepitant and reveal their influence of laboratory tests and cytochrome P450 (CYP) 3A5 gene polymorphisms in cancer patients. Forty-four Japanese cancer patients receiving cisplatin-based chemotherapy for the first time following oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) were enrolled.

Hydroxy-itraconazole pharmacokinetics is similar to that of itraconazole in immunocompromised patients receiving oral solution of itraconazole.

Background: The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole (ITZ), is not fully known.

Methods: Oral solution of ITZ was administered in 46 immunocompromised patients as a single 200 mg dose for at least 12 days. The plasma concentrations of ITZ, active OH-ITZ, and keto-itraconazole (keto-ITZ), an inactive metabolite, 12 h after administration were determined by LC-UV or LC-MS/MS.

Impact of CYP3A5 genetic polymorphism on cross-reactivity in tacrolimus chemiluminescent immunoassay in kidney transplant recipients.

Background: Tacrolimus immunoassays possess cross-reactivity with metabolites in the blood. The aim of this study was to evaluate the cross-reactivity in tacrolimus chemiluminescent immunoassay (CLIA) in kidney transplant recipients and to characterize the cross-reactivity according to CYP3A5 genetic polymorphism.

Methods: The subjects were 50 kidney transplant recipients receiving low-dose tacrolimus.

Impact of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system.

The aim of this study was to evaluate the influence of CYP3A5 and ABCB1 gene polymorphisms on fentanyl pharmacokinetics and clinical responses in cancer patients undergoing conversion to a transdermal system. Sixty Japanese cancer patients being treated with a fentanyl transdermal reservoir system according to the current Japanese guidelines were enrolled. Blood samples were obtained 192 h after conversion to the fentanyl transdermal system.

Impact of concomitant antacid administration on gabapentin plasma exposure and oral bioavailability in healthy adult subjects.

The aim of this open-label, randomized, and 3-period crossover study was to evaluate the influences of concomitant antacid administration on the plasma disposition, intestinal absorption, and urinary excretion of gabapentin in humans. Gabapentin (200 mg) was orally administered alone, with 1 g magnesium oxide (MgO), or with 20 mg omeprazole to 13 healthy adult subjects. Oral bioavailability (BA) of gabapentin was estimated by 24-h urine collection.

Rapid simultaneous determination of voriconazole and its N-oxide in human plasma using an isocratic high-performance liquid chromatography method and its clinical application.

Objectives: The aim of this study was to develop a simultaneous determination method for voriconazole (VRCZ) and its N-oxide (VNO) in human plasma and to apply it to clinical samples.

Design And Methods: Plasma specimens were deproteinized with acetonitrile and then injected into an HPLC-UV system. VRCZ and VNO were separated on an ODS column filled with 2.

Pharmacokinetic variability of mycophenolic acid and its glucuronide in systemic lupus erythematosus patients in remission maintenance phase.

The aim of this study was to identify factors affecting the pharmacokinetics of mycophenolic acid (MPA) and its 7-O-glucuronide (MPAG) in systemic lupus erythematosus (SLE) patients. Thirty-one SLE patients in remission maintenance phase treated with mycophenolate mofetil (median 1500 mg/d) and prednisolone and followed-up for up to 56 months (median 13 months) were enrolled. Creatinine clearance and metal medication were significant predictors accounting for interindividual variability in the dose-normalized predose plasma concentration (C₀) of MPA (adjusted R²=0.

Suitability of chemiluminescent enzyme immunoassay for the measurement of blood tacrolimus concentrations in rheumatoid arthritis.

Objectives: The aim of this study was to evaluate the suitability of chemiluminescent enzyme immunoassay (CLIA) for the monitoring of whole-blood tacrolimus concentrations in rheumatoid arthritis (RA) patients.

Design And Methods: Sixty-three RA patients and 47 renal transplant (RT) patients treated with tacrolimus were enrolled. Tacrolimus concentrations in spiked blood and patient blood were measured by CLIA and HPLC-MS/MS.

Impact of concentrative nucleoside transporter 1 gene polymorphism on oral bioavailability of mizoribine in stable kidney transplant recipients.

Mizoribine, an immunosuppressive anti-metabolite, is largely excreted into urine in its unchanged form, and its pharmacokinetics has been considered to be dependent on the glomerular filtration rate. However, the pharmacokinetic disposition of mizoribine has not been fully clarified. The aim of this study was to evaluate the pharmacokinetic disposition of mizoribine based on polymorphism of concentrative nucleoside transporter (CNT) 1 gene in kidney transplant recipients.

Inosine monophosphate dehydrogenase activity depends on plasma concentrations of mycophenolic acid and its glucuronides in kidney transplant recipients.

Background: Inosine 5'-monophosphate dehydrogenase (IMPDH) is a target of the immunosuppressant mycophenolic acid (MPA) which is used for the prevention of acute rejection. We evaluated the concentration-dependent effects of MPA and its phenolic (MPAG) and acyl (AcMPAG) glucuronides on IMPDH activity in erythrocytes in an initial and a stable phase.

Methods: Eight kidney transplant recipients treated with mycophenolate mofetil (MMF) in an initial phase and 104 recipients [56 received MMF (MMF+) and 48 did not (MMF-)] in a stable phase were enrolled.

Impact of calcineurin inhibitors on urinary excretion of mycophenolic acid and its glucuronide in kidney transplant recipients.

Concomitant cyclosporine interacts with mycophenolic acid (MPA) through inhibition of the biliary excretion of its glucuronide (MPAG). The aim of this study was to evaluate the influence of calcineurin inhibitors on the plasma disposition and urinary excretion of MPA and MPAG in kidney transplant recipients. Twelve recipients treated with tacrolimus and 18 treated with cyclosporine at 30 days after transplantation were enrolled.

Cyclosporine concentration-dependent increase in concentration ratio of mycophenolic acid acyl and phenol glucuronides to mycophenolic acid in stable kidney transplant recipients.

Objectives: The aim of this study was to evaluate the influence of cyclosporine (CyA) and tacrolimus (Tac) on the pharmacokinetics of mycophenolic acid (MPA) and its glucuronides.

Design And Methods: Kidney transplant recipients treated with mycophenolate mofetil and CyA (n=18) or Tac (n=17) in the stable phase were enrolled. The dependence of the trough concentration (C(0)) ratios of MPA acyl glucuronide (AcMPAG) to MPA (AcMPAG/MPA) and MPA phenol glucuronide (MPAG) to MPA (MPAG/MPA) on CyA C(0) or Tac C(0) was evaluated.

Comparison of pharmacokinetics of mycophenolic acid and its glucuronide between patients with lupus nephritis and with kidney transplantation.

The pharmacokinetics of mycophenolic acid (MPA) and its glucuronide (mycophenolic acid phenolic glucuronide, MPAG) in lupus nephritis (LN) have not been fully characterized. The aim of this study was to evaluate the pharmacokinetics of MPA and MPAG in LN patients by comparing the pharmacokinetics with those of kidney transplant (KT) recipients. Six LN patients (World Health Organization class IV and V) and 24 KT recipients [8 recipients treated with tacrolimus (Tac) and 16 with cyclosporine (CyA)] during the early posttransplantation period were enrolled.