Global Pharmaceutical Research and Development

Waukegan, IL, United States

Global Pharmaceutical Research and Development

Waukegan, IL, United States

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Asahina A.,Jikei University School of Medicine | Ohtsuki M.,Jichi Medical University | Etoh T.,Tokyo Teishin Postal Services Agency Hospital | Gu Y.,Global Pharmaceutical Research and Development | And 4 more authors.
Journal of Dermatology | Year: 2015

The tumor necrosis factor-α inhibitor, adalimumab, is approved to treat moderate-to-severe plaque psoriasis (40 mg every-other-week or 80 mg every-other-week following inadequate response at 40 mg in Japan). This open-label extension (OLE) trial evaluated the optimal adalimumab dose for long-term efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis following a prior 24-week, phase 2/3, randomized, double-blind study. Of the 169 patients from the phase 2/3 trial, 147 entered the OLE on 40 mg (n = 89) or 80 mg (n = 58) adalimumab every-other-week. Patients on 40 mg with Psoriasis Area and Severity Index (PASI) of less than 50 could escalate to 80 mg. At week 52 (28 of OLE), patients entering the OLE on 80 mg were reduced to 40 mg, with the option to re-escalate. For patients entering the OLE on 40 mg, final PASI 50/75/90 response rates were 85.1%/73.3%/60.4%, respectively, including effects of dose escalation. Among patients whose dose was escalated, final PASI 50/75/90 response rates were 70.0%/53.3%/36.7%, respectively. For patients entering the OLE on 80 mg, final PASI 50/75/90 response rates were 92.5%/84.9%/73.6%, respectively, including effects of dose re-escalation. Overall incidence rates of adverse events (AE) and injection-site reaction AE declined over time; rates for serious AE and infections were generally stable. Clinically meaningful efficacy of adalimumab was sustained to 4 years. Dose escalation to 80 mg every-other-week for patients with suboptimal response to 40 mg every-other-week, and dose reduction to 40 mg every-other-week for patients satisfactorily controlled on 80 mg every-other-week, are viable strategies for adalimumab optimization. © 2015 Japanese Dermatological Association.


Beig A.,Ben - Gurion University of the Negev | Miller J.M.,Global Pharmaceutical Research and Development | Dahan A.,Ben - Gurion University of the Negev
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2013

The purpose of this study was to investigate the interaction of 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 2,6-dimethyl-β- cyclodextrin (DMβCD) with the lipophilic drug nifedipine and to investigate the subsequent solubility-permeability interplay. Solubility curves of nifedipine with HPβCD and DMβCD in MES buffer were evaluated using phase solubility methods. Then, the apparent permeability of nifedipine was investigated as a function of increasing HPβCD/DMβCD concentration in the hexadecane-based PAMPA model. The interaction with nifedipine was CD dependent; significantly higher stability constant was obtained for DMβCD in comparison with HPβCD. Moreover, nifedipine displays different type of interaction with these CDs; a 1:1 stoichiometric inclusion complex was apparent with HPβCD, while 1:2 stoichiometry was apparent for DMβCD. In all cases, decreased apparent intestinal permeability of nifedipine as a function of increasing CD level and nifedipine apparent solubility was obtained. A quasi-equilibrium mass transport analysis was developed to explain this solubility-permeability interplay; the model enabled excellent quantitative prediction of nifedipine's permeability as a function of CD concentrations. This work demonstrates that when using CDs in solubility-enabling formulations, a trade-off exists between solubility increase and permeability decrease that must not be overlooked. This trade-off was found to be independent of the type of CD-drug interaction. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption. © 2013 Elsevier B.V. All rights reserved.


Chiou W.J.,Global Pharmaceutical Research and Development | De Morais S.M.,Global Pharmaceutical Research and Development | Kikuchi R.,Global Pharmaceutical Research and Development | Voorman R.L.,Global Pharmaceutical Research and Development | And 2 more authors.
Xenobiotica | Year: 2014

1. Transient benign unconjugated hyperbilirubinemia has been observed clinically with several drugs including indinavir, cyclosporine, and rifamycin SV. Genome-wide association studies have shown significant association of OATP1B1 and UGT1A1 with elevations of unconjugated bilirubin, and OATP1B1 inhibition data correlated with clinical unconjugated hyperbilirubinemia for several compounds. 2. In this study, inhibition of OATP1B3 and UGT1A1, in addition to OATP1B1, was explored to determine whether one measure offers value over the other as a potential prospective tool to predict unconjugated hyperbilirubinemia. OATP1B1 and OATP1B3-mediated transport of bilirubin was confirmed and inhibition was determined for atazanavir, rifampicin, indinavir, amprenavir, cyclosporine, rifamycin SV and saquinavir. To investigate the intrinsic inhibition by the drugs, both in vivo Fi (fraction of intrinsic inhibition) and R-value (estimated maximum in vivo inhibition) for OATP1B1, OATP1B3 and UGT1A1 were calculated. 3. The results indicated that in vivo Fi values >0.2 or R-values >1.5 for OATP1B1 or OATP1B3, but not UGT1A1, are associated with previously reported clinical cases of drug-induced unconjugated hyperbilirubinemia. 4. In conclusion, inhibition of OATP1B1 and/or OATP1B3 along with predicted human pharmacokinetic data could be used pre-clinically to predict potential drug-induced benign unconjugated hyperbilirubinemia in the clinic. © 2014 Informa UK Ltd.


Renjifo B.,Global Pharmaceutical Research and Development | Van Wyk J.,Global Pharmaceutical Research and Development | Salem A.H.,Global Pharmaceutical Research and Development | Bow D.,Global Pharmaceutical Research and Development | And 2 more authors.
AIDS Reviews | Year: 2014

Inhibition of the cytochrome p450 3A4 enzyme system leads to increases in plasma concentrations of coadministered antiretroviral agents - a concept known as pharmacokinetic boosting. Ritonavir and cobicistat are potent inhibitors of cytochrome p450 3A4. Ritonavir was initially developed as an HIV protease inhibitor, but is currently used primarily as a pharmacokinetic boosting agent for other HIV and hepatitis C protease inhibitors. Cobicistat is a boosting agent for the integrase inhibitor elvitegravir and the protease inhibitors atazanavir and darunavir. Phase III data showed that atazanavir + cobicistat + tenofovir/emtricitabine had non-inferior efficacy and resulted in similar CD4 T-cell count increases to atazanavir + ritonavir + tenofovir/emtricitabine. The tolerability, gastrointestinal, and lipid profile of the cobicistat-containing regimen was comparable with the ritonavir-containing regimen. Primary HIV protease resistance mutations were not selected in either ritonavir or cobicistat arm virologic failures. Cobicistat-containing regimens have consistently shown higher serum creatinine increases and creatinine clearance decreases compared with ritonavir, and accurate assessment of glomerular filtration in the presence of cobicistat could only be made by using exogenous markers such as iohexol. Drugs contraindicated with cobicistat are consistent with those contraindicated with ritonavir-containing protease inhibitor regimens with respect to cytochrome p450 3A interactions. Information in this review may help clinicians assess the benefits and limitations of currently available pharmacokinetic enhancers when selecting the most appropriate treatment for their patients.

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