Similar findings of discordance between CYP3A inhibition and induction have been reported for several drugs, including ixazomib,17 tivozanib,18 and vandetanib19; this contrast has 1 of 2 possible main explanations

Similar findings of discordance between CYP3A inhibition and induction have been reported for several drugs, including ixazomib,17 tivozanib,18 and vandetanib19; this contrast has 1 of 2 possible main explanations. cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in Benfluorex hydrochloride 3 parts of an open\label, nonrandomized, 2\period, single\sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration\time curve from time 0 to infinity (AUC0\inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0\inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0\inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin. polymorphism on the enzyme activity have been investigated. The allele (?163C A in intron 1) is commonly identified with high and comparable frequencies across various populations7 and confers higher enzyme inducibility of CYP1A2 in smokers.8, 9 (?163C A, ?739T G, and ?729C T in intron 1) is associated with lower CYP1A2 activity compared with the wild type in nonsmokers.10 CYP1A2 more generally is highly inducible at both the mRNA and protein levels by a variety of chemicals, smoking, and several dietary factors through the aromatic hydrocarbon receptor.11 To minimize the variability in CYP1A2 activity caused by genetic and environmental factors, homozygotes, heterozygotes and homozygotes, and smokers ( 10 cigarettes per day, or the equivalent in other tobacco products [self\reported]) were excluded from Benfluorex hydrochloride this study. In addition, subjects who had a allele were excluded. Study Design and Treatment Part 2: CYP3A Inhibition This was an open\label, nonrandomized, 2\period, single\sequence crossover study to evaluate the effect Benfluorex hydrochloride of coadministration of itraconazole (as oral solution), a strong CYP3A inhibitor, on avadomide PK in healthy adult subjects. Period?1 (avadomide only) spanned days C1 to 4, whereas period?2 (avadomide with itraconazole) subsequently spanned days C1 to 7 (Figure S1A). Eligible subjects checked in to the study center on day C1 of period 1 and remained domiciled at the study center through day 7 of period 2. All enrolled subjects received the same dosing regimen under fasted conditions: a single oral dose of 3 mg avadomide in the morning of day 1 of period 1; once daily (QD) oral dose of 200 mg itraconazole from days 1 to 3 of period 2; a single oral dose of 3 mg avadomide in the morning plus 1 oral dose of 200 mg itraconazole on day 4 of period 2; and oral doses of 200 mg itraconazole QD from days 5 to 6 of period 2. There was a washout period of 5 days between the dose on day 1 of period 1 and the first dose administration in period 2 (day 1 of period 2). Subjects were discharged from the study center on day 7 of period 2 on satisfactory safety review and on completion of study\related procedures. The itraconazole dose, dosage form, and duration used in this study were all based on the published data review of Liu et?al.12 Part 3: CYP1A2 Inhibition This was an open\label, nonrandomized, 2\period, single\sequence crossover study to evaluate the effect of coadministration of fluvoxamine, a strong CYP1A2 inhibitor, on avadomide PK in healthy adult subjects. Period 1 (avadomide only) spanned days C1 to 4; whereas period 2 (avadomide with fluvoxamine) subsequently spanned days C1 to 8 (Figure S1B). Eligible subjects checked in to the study center on day C1 of period 1 and remained domiciled there Benfluorex hydrochloride through day 8 of period 2. All enrolled subjects received the same dosing regimen under fasted conditions: a single oral dose of 3 mg avadomide in the morning of day 1 of period 1; twice daily (BID) oral doses of 50 mg fluvoxamine from days 1 to 4 of period 2; a single oral dose of 3 mg avadomide in the morning plus BID.The larger impact on AUC than Cmax suggests that fluvoxamine mainly contributes to the inhibition of avadomide clearance by hepatic CYP1A2 and, to a lesser extent, the inhibition of intestinal CYP1A2, supported by the finding that fluvoxamine coadministration prolonged avadomide t? by 50% and decreased apparent clearance by 34% with less pronounced increases in tmax and Cmax. Rifampin (oral capsule) was used as a CYP3A4 perpetrator because it is a well\documented strong CYP3A4 inducer.16 Rifampin, when administered as a dose of 600 mg QD for 10 days, was anticipated to induce CYP3A4 and used to evaluate the effect of strong CYP3A4 induction on the PK of avadomide. single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration\time curve from time 0 to infinity (AUC0\inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0\inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0\inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin. polymorphism on the enzyme activity have been investigated. The allele (?163C A in intron 1) is commonly identified with high and comparable frequencies across various populations7 and confers higher enzyme inducibility of CYP1A2 in smokers.8, 9 (?163C A, ?739T G, and ?729C T in intron 1) is associated with lower CYP1A2 activity compared with the wild type in nonsmokers.10 CYP1A2 more generally is highly inducible at both the mRNA and protein levels by a variety of chemicals, smoking, and several dietary factors through the aromatic hydrocarbon receptor.11 To minimize the variability in CYP1A2 activity caused by genetic and environmental factors, homozygotes, heterozygotes and homozygotes, and smokers ( 10 cigarettes per day, or the equivalent in other tobacco products [self\reported]) were excluded from this study. In addition, subjects who had a allele were excluded. Study Design and Treatment Part 2: CYP3A Inhibition This was an open\label, nonrandomized, Benfluorex hydrochloride 2\period, single\sequence crossover study to evaluate the effect of coadministration of itraconazole (as oral solution), a strong CYP3A inhibitor, on avadomide PK in healthy adult subjects. Period?1 (avadomide only) spanned days C1 to 4, whereas period?2 (avadomide with itraconazole) subsequently spanned days C1 to 7 (Figure S1A). Eligible subjects checked in to the study center on day C1 of period 1 and remained domiciled at the study center through day 7 of period 2. All enrolled subjects received the same dosing regimen under fasted conditions: a single oral dose of 3 mg avadomide in the morning of day 1 of period 1; once daily (QD) oral dose of 200 mg itraconazole from days 1 to 3 of period 2; a single oral dose of 3 mg avadomide in the morning plus 1 oral dose of 200 mg itraconazole on day 4 of period 2; and oral doses of 200 mg itraconazole QD from days 5 to 6 of period 2. There was a washout period of 5 days between the dose on day 1 of period 1 and the first dose administration in period 2 (day 1 of period 2). Subjects were discharged from the study center on day 7 of period 2 on satisfactory safety review and on completion of study\related procedures. The itraconazole dose, dosage form, and duration used in this study were all based on the published data review of Liu et?al.12 Part 3: CYP1A2 Inhibition Cd14 This was an open\label, nonrandomized, 2\period, single\sequence crossover study to evaluate the effect of coadministration of fluvoxamine, a strong CYP1A2 inhibitor, on avadomide PK in healthy adult subjects. Period 1 (avadomide only) spanned days C1 to 4; whereas period 2 (avadomide with fluvoxamine) subsequently spanned days C1 to.