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Suttle A.B.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Grossmann K.F.,Huntsman Cancer InstituteUniversity of UtahSalt Lake City | Ouellet D.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Richards-Peterson L.E.,GlaxoSmithKlineCollegevillePAUSA | And 12 more authors.
Journal of Clinical Pharmacology | Year: 2015

The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC0-∞ decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC0-τ and Cmax increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC0-τ increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC0-τ increased 47%, with no change in Cmax, after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib. © 2014, The American College of Clinical Pharmacology.

Jewell R.C.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Laubscher K.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Lewis E.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Fang L.,Pharstat Inc.Raleigh | And 9 more authors.
Journal of Clinical Pharmacology | Year: 2014

Ofatumumab is a human monoclonal antibody that binds to a unique CD20 epitope on the surface of B lymphocytes, resulting in efficient lysis of CD20-expressing cells via complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The potential effect of ofatumumab on cardiac repolarization and the relationship between ofatumumab concentration and change in corrected QT interval (ΔQTcF) were evaluated in data from three clinical trials in 82 patients with chronic lymphocytic leukemia receiving ofatumumab alone (n=14), ofatumumab with chemotherapy (n=33), and chemotherapy alone (n=35). Because of ofatumumab accumulation, baseline QTcF interval was recorded prior to the first infusion for each patient. No patient had a post-baseline QTcF interval >480 milliseconds or a ΔQTcF >60 milliseconds; five patients (four on ofatumumab) had a ΔQTcF between 30 and 60 milliseconds. At cycle 6 (week 21; 308μg/mL), there was an increase in QTcF in patients on ofatumumab treatment, with an estimated between-treatment difference (90% CI) of 12.5 (4.5, 20.5) milliseconds. However, at the visit with the highest median concentration (week 8; 1386μg/mL), median ΔQTcF was 4.8 milliseconds. There was no significant relationship between ofatumumab plasma concentration and ΔQTcF. Ofatumumab did not have a clinically significant effect on cardiac repolarization. © 2014, The American College of Clinical Pharmacology.

Song I.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Borland J.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Arya N.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Wynne B.,GlaxoSmithKlineResearch Triangle ParkNCUSA | Piscitelli S.,GlaxoSmithKlineResearch Triangle ParkNCUSA
Journal of Clinical Pharmacology | Year: 2015

All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) dolutegravir alone, fasting; (2) dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) dolutegravir administered 2hours before calcium carbonate or ferrous fumarate, fasting. Plasma dolutegravir AUC(0-∞), Cmax, and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, dolutegravir should be administered 2hours before or 6hours after calcium or iron supplements. © 2014, The American College of Clinical Pharmacology.

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