Publications by authors named "Ogert Fisniku"

8 Publications

  • Page 1 of 1

Characterization of the Effect of Upadacitinib on the Pharmacokinetics of Bupropion, a Sensitive Cytochrome P450 2B6 Probe Substrate.

Clin Pharmacol Drug Dev 2021 03 9;10(3):299-306. Epub 2020 Jul 9.

AbbVie Inc., North Chicago, Illinois, USA.

This phase 1 study characterized the effect of multiple doses of upadacitinib, an oral Janus kinase 1 selective inhibitor, on the pharmacokinetics of the cytochrome P450 (CYP) 2B6 substrate bupropion. Healthy subjects (n = 22) received a single oral dose of bupropion 150 mg alone (study period 1) and on day 12 of a 16-day regimen of upadacitinib 30 mg once daily (study period 2). Serial blood samples for measurement of bupropion and hydroxybupropion plasma concentrations were collected in each study period. The central values (90% confidence intervals) for the ratios of change were 0.87 (0.79-0.96) for bupropion maximum plasma concentration (C ), 0.92 (0.87-0.98) for bupropion area under the plasma-concentration time curve from time 0 to infinity (AUC ), 0.78 (0.72-0.85) for hydroxybupropion C , and 0.72 (0.67-0.78) for hydroxybupropion AUC when administered with, relative to when administered without, upadacitinib. After multiple-dose administration of upadacitinib 30 mg once daily, upadacitinib mean ± SD AUC was 641 ± 177 ng·h/mL, and C was 83.3 ± 30.7 ng/mL. These results confirm that upadacitinib has no relevant effect on pharmacokinetics of substrates metabolized by CYP2B6.
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http://dx.doi.org/10.1002/cpdd.844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984436PMC
March 2021

Effects of Upadacitinib Coadministration on the Pharmacokinetics of Sensitive Cytochrome P450 Probe Substrates: A Study With the Modified Cooperstown 5+1 Cocktail.

J Clin Pharmacol 2020 01 5;60(1):86-95. Epub 2019 Aug 5.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.

The aim of this study was to characterize the effects of upadacitinib, a Janus kinase 1 inhibitor, on in vivo activity of different cytochrome P450 (CYP) enzymes using a cocktail approach. Healthy subjects (n = 20) received single oral doses of the modified Cooperstown 5+1 cocktail drugs (midazolam [CYP3A], caffeine [CYP1A2], warfarin + vitamin K [CYP2C9], omeprazole [CYP2C19], and dextromethorphan [CYP2D6]) without upadacitinib and on day 11 (midazolam) or 12 (all other probes) of a 15-day regimen of upadacitinib 30 mg once daily (extended-release formulation). Serial blood samples and 12-hour urine samples were collected for assays of the probe substrates and select metabolites. The ratio (90%CI) of area under the plasma concentration-time curve from time 0 to infinity (AUC ) central values when the cocktail drugs were administered with upadacitinib relative to when administered alone were 0.74 (0.68-0.80) for midazolam, 1.22 (1.15-1.29) for caffeine, 1.11 (1.07-1.15) for S-warfarin, 1.07 (0.95-1.22) for dextromethorphan, and 0.82 (0.72-0.94) for omeprazole. The ratio (90%CI) was 1.09 (1.00-1.19) for 5-hydroxy-omeprazole to omeprazole AUC ratio and 1.17 (0.97-1.41) for dextromethorphan to dextrorphan 12-hour molar urinary ratio. Upadacitinib 30 mg once daily (a dose that is twice the optimal dose in rheumatoid arthritis based on phase 3 results) has a limited effect on CYP3A activity (26% decrease in exposure of midazolam, a sensitive CYP3A substrate) and no relevant effects on CYP1A2, CYP2C9, CYP2C19, or CYP2D6 activity in vivo. No clinically relevant changes in plasma exposures are expected for drugs that are substrates for the evaluated CYP enzymes when coadministered with upadacitinib.
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http://dx.doi.org/10.1002/jcph.1496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972567PMC
January 2020

The Effect of Verapamil, a P-Glycoprotein Inhibitor, on the Pharmacokinetics of Peficitinib, an Orally Administered, Once-Daily JAK Inhibitor.

Clin Pharmacol Drug Dev 2017 Nov 16;6(6):548-555. Epub 2017 Mar 16.

Astellas Pharma Global Development Inc., Northbrook, IL, USA.

Peficitinib is an orally administered, once-daily Janus kinase inhibitor currently in development for the treatment of rheumatoid arthritis. It has been shown to be a P-glycoprotein (P-gp) substrate in vitro. The effects of verapamil, an inhibitor of the efflux pump P-gp, on the pharmacokinetic profile of peficitinib were assessed in this open-label, single-center, single-sequence, crossover drug-interaction study. Twenty-four healthy volunteers received a single 150-mg dose of peficitinib on days 1 and 12 of a 14-day treatment period and received verapamil 80 mg 3 times daily on days 5-14. Repeated-dose administration of verapamil increased mean peficitinib AUC , AUC , and C by 27%, 27%, and 39%, respectively, and also increased the mean AUC and C of peficitinib metabolites H1, H2, and H4. Coadministration of verapamil with peficitinib 150 mg was generally well tolerated. Overall, the most commonly reported adverse event was headache, which occurred in 5 subjects (21%); all reported adverse events were grade 1 severity, with the exception of 1 grade 2 incident of vomiting.
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http://dx.doi.org/10.1002/cpdd.344DOI Listing
November 2017

Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects.

Clin Pharmacokinet 2017 07;56(7):747-757

Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Inc., 1 Astellas Way, Northbrook, IL, 60062, USA.

Background And Objective: Peficitinib is an orally administered, once-daily Janus kinase inhibitor in development for the treatment of rheumatoid arthritis. Peficitinib and its major metabolite H2 inhibit the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1) in vitro. This article reports a clinical study evaluating the effects of peficitinib on the pharmacokinetics of rosuvastatin, a substrate for the OATP1B1 transporter, and vice versa.

Methods: In an open-label, single-sequence clinical study, 24 healthy adults of East Asian and non-East Asian origin received a single dose of rosuvastatin 10 mg on days 1 and 10. On days 5-13, subjects received a daily dose of 150 mg peficitinib. Serial blood samples for pharmacokinetic assessment of rosuvastatin were collected up to 96 h post-dose on days 1 and 10, and for peficitinib were collected up to 24 h post-dose on days 9 and 10.

Results: Co-administration of peficitinib with rosuvastatin increased rosuvastatin area under the concentration-time curve (AUC) and maximum plasma concentration (C ) by 18 and 15%, respectively and increased peficitinib AUC and C by 16 and 28%, respectively. In East Asian (n = 6) vs. non-East Asian subjects (n = 18), peficitinib mean AUC for a dosing interval was 45 and 21% higher, and mean C was 67 and 34% higher, when administered alone or with rosuvastatin. Peficitinib was well tolerated with few adverse events overall.

Conclusion: In this study, once-daily oral administration of peficitinib had no clinically significant effect on the pharmacokinetics of rosuvastatin, a probe substrate for OATP1B1. Therefore, it is unlikely that peficitinib will have a clinically significant effect on the exposure of other substrates for OATP1B1. CLINICALTRIALS.

Gov Number: NCT01959399.
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http://dx.doi.org/10.1007/s40262-016-0474-4DOI Listing
July 2017

Human mass balance, metabolite profile and identification of metabolic enzymes of [¹⁴C]ASP015K, a novel oral janus kinase inhibitor.

Xenobiotica 2015 19;45(10):887-902. Epub 2015 May 19.

a Analysis & Pharmacokinetics Research Laboratories, Astellas Pharma Inc. , Osaka , Japan .

1. The human mass balance of (14)C-labelled ASP015K ([(14)C]ASP015K), an orally bioavailable Janus kinase (JAK) inhibitor, was characterized in six healthy male subjects after a single oral dose of [(14)C]ASP015K (100 mg, 3.7 MBq) in solution. [(14)C]ASP015K was rapidly absorbed with tmax of 1.6 and 1.8 h for ASP015K and total radioactivity in plasma, respectively. Mean recovery in urine and feces amounted to 36.8% and 56.6% of the administered dose, respectively. The main components of radioactivity in plasma and urine were ASP015K and M2 (5'-O-sulfo ASP015K). In feces, ASP015K and M4 (7-N-methyl ASP015K) were the main components. 2. In vitro study of ASP015K metabolism showed that the major isozyme contributing to the formation of M2 was human sulfotransferase (SULT) 2A1 and of M4 was nicotinamide N-methyltransferase (NNMT). 3. The in vitro intrinsic clearance (CLint_in vitro) of M4 formation from ASP015K in human liver cytosol (HLC) was 11-fold higher than that of M2. The competitive inhibitory effect of nicotinamide on M4 formation in the human liver was considered the reason for high CLint_in vitro of M4 formation, while each metabolic pathway made a near equal contribution to the in vivo elimination of ASP015K. ASP015K was cleared by multiple mechanisms.
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http://dx.doi.org/10.3109/00498254.2015.1026864DOI Listing
June 2016

A blocking anti-CD28-specific antibody induces long-term heart allograft survival by suppression of the PKC theta-JNK signal pathway.

Transplantation 2008 Apr;85(7):1051-5

Astellas Research Institute of America, Skokie, IL 60077, USA.

This study investigated the effects of a blocking anti-CD28 antibody (Anti-CD28-PV1-IgG3) in vitro and in vivo. Anti-CD28-PV1-IgG3, a hamster-mouse chimeric antibody against murine CD28, which does not provide CD28-positive signaling during TCR-driven T cell activation, enabled long-term survival of heart allografts across a complete mismatch of the MHC in rats. Among the T cell signaling proteins tested in the spleens from recipients, we found that recipients treated with anti-CD28-PV1-IgG3 exhibited suppression of alloantigen-initiated proximal TCR signaling events, including Lck, Zap70, Vav, and PI3K expression, and their PKC theta- and JNK-regulated expression/activation. This leads to attenuation of intragraft T cell infiltration and expression of T cell effector molecules. These results indicate that targeting the CD28 receptor with a blocking antibody leads to long-term allograft survival by reducing activation of alloantigen-mediated key signaling events in T cells that might be crucial for full T cell activation.
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http://dx.doi.org/10.1097/TP.0b013e31816846f6DOI Listing
April 2008

Unique gene expression profiles of heart allograft rejection in the interferon regulatory factor-1-deficient mouse.

Transpl Immunol 2004 Nov;13(3):169-75

Fujisawa Research Institute of America, 1801 Maple Avenue, Evanston, IL 60201, USA.

Interferon regulatory factor-1 (IRF1) is a transcription factor for many genes involved in innate and adaptive immune responses. By using DNA array technology, we have previously demonstrated that IRF1 is significantly upregulated during acute rejection in rat heart allografts and is restored to isograft levels when recipients are treated with the immunosuppressants tacrolimus or cyclosporin A (CsA). To understand the precise role of IRF1 in transplant rejection, we investigated the rejection responses of mice completely deficient of IRF1 protein. Heterotopic heart transplantations were performed using C57BL/6J wild-type (WT B6) and IRF1-deficient (IRF1-/-) mice as recipients, and C3H mice as donors. Graft survival was determined by abdominal palpation and rejection was confirmed by histology. On day 6 after transplantation, isografts and allografts were harvested and subjected to gene expression analysis by a commercial nylon array and by real-time RT-PCR. Median survival time of heart allografts was 8 days in the WT B6 mice and 10 days in the IRF1-/- mice. The gene expression profiles of allografts from the WT B6 and IRF1-/- recipients were nearly identical to each other and very different from the profile of the isograft control. Both WT B6 and IRF1-/- profiles showed 13 genes upregulated (IFN-gamma, MCP-2, MIP-1alpha, MIP-1beta, CCR5, MIG, IP-10 and others) and one gene downregulated (SDF2) among the 76 genes detectable on the array. In more detailed analyses, distinct cytokine and chemokine gene expression profiles were identified in the allografts from the WT B6 and IRF1-/- recipients. Whereas IL-4, IL-6, IL-13, MCP-1, MCP-3, and MPIF-2 were upregulated, RANTES, IL-2Rgamma and gp130 were downregulated in allografts from the IRF1-/- recipients when compared to the WT B6 control. Although the inactivation of the IRF1 gene did not sufficiently prevent acute allograft rejection in this model, a unique cytokine and chemokine gene expression profile was found in the absence of IRF1.
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http://dx.doi.org/10.1016/j.trim.2004.06.003DOI Listing
November 2004

FK778, a powerful new immunosuppressant, effectively reduces functional and histologic changes of chronic rejection in rat renal allografts.

Transplantation 2003 Apr;75(8):1110-4

Basic Science, Fujisawa Research Institute of America, Evanston, IL 60201-3135, USA.

Background: FK778 is a new derivative of the active leflunomide metabolite A77 1726. It effectively prevented acute allograft rejection in several experimental transplant models, and it is currently in phase II trials in human transplant recipients. In this study, we examined the effects of FK778 in a well-established model of chronic renal allograft rejection in the rat.

Methods: Kidneys of Lewis (LEW) and F344 rats were orthotopically transplanted into bilaterally nephrectomized LEW recipients as the isograft and allograft control, respectively. Allograft recipients were orally administered FK778 at doses of 3 mg/kg per day, 10 mg/kg per day, and 20 mg/kg per day for 10 days. Blood and 24-hr urine samples were collected once a week after grafting for plasma creatinine, allo-specific antibodies, and proteinuria determination. Kidney grafts were harvested on the 90th day after transplantation and subjected to histologic, immunohistologic, and reverse transcriptase-polymerase chain reaction analysis. Histologic sections were semiquantitatively scored using criteria adapted from the Banff' classification for transplant pathologic conditions.

Results: Recipients treated with FK778 for 10 days exhibited a dose-dependent decrease in proteinuria and plasma creatinine for the entire 90-day period after transplantation when compared with the allograft control. FK778, at doses of 10 mg/kg per day and 20 mg/kg per day, remarkably reduced chronic histologic changes, including tubular atrophy, glomerulosclerosis, fibrointimal hyperplasia, and transplant glomerulopathy. In addition, FK778 treatment was associated with decreased intragraft mononuclear cell infiltration, serum allo-specific immunoglobulin (Ig)M and IgG antibody production, and intragraft transforming growth factor beta messenger RNA expression in those recipients surviving 90 days after transplantation when compared with the allograft control.

Conclusion: FK778 effectively reduces functional and histologic chronic kidney allograft rejection in the rat.
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http://dx.doi.org/10.1097/01.TP.0000063704.19149.E3DOI Listing
April 2003
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