Pharmacokinetics of coadministration of levothyroxine sodium and alendronate sodium new effervescent formulation

Osteoporosis International, Feb 2017

Summary No clinically important pharmacokinetic interference of alendronate occurred between a new effervescent formulation of alendronate and levothyroxine when coadministered. The combination does not materially affect levothyroxine absorption. Introduction Concurrent treatment of osteoporosis with alendronate (Aln) and hypothyroidism with levothyroxine (LT4) may be problematic because both drugs are to be taken separately after fasting overnight. The primary objective was to assess pharmacokinetic interactions between a new effervescent formulation of Aln (Aln-NEF) and LT4. Methods A randomized, open-label, 3-way crossover study was conducted in 30 healthy adults (15 women). Subjects were dosed 3 times, separated by 35 days, after overnight fasts, with Aln-NEF alone (70 mg), LT4 alone (600 μg), or Aln-NEF and LT4 concurrently. Samples were analyzed for plasma Aln and serum LT4. Pharmacokinetic drug-drug interaction was assessed using 90% confidence intervals (CIs) for the test/reference ratio of the geometric means for area under the concentration-time curve from time zero to last measureable time point (AUC0-t ) and maximum concentration (C max). Results were compared to the default no-effect boundaries of 80 to 125% for the ratio Aln-NEF and LT4 concurrently/Aln-NEF alone and the ratio Aln-NEF and LT4 concurrently/LT4 alone. Results Geometric mean ratios (Aln-NEF with LT4/Aln-NEF alone) were 0.927 (90% CI 0.795–1.081) for AUC0–8 and 0.912 (90% CI 0.773–1.077) for C max, demonstrating LT4 does not appreciably affect the pharmacokinetics of Aln. Geometric mean ratios (LT4 with Aln-NEF/LT4 alone) were 1.049 (90% CI 0.983–1.119) for AUC0–48 and 1.075 (90% CI 1.006–1.148) for C max, demonstrating LT4 is bioequivalent between the 2 treatments. Coadministration of Aln-NEF and LT4 was well tolerated. Conclusions There was no clinically important pharmacokinetic interference between the Aln-NEF formulation and LT4. Aln-NEF does not materially affect LT4 absorption.

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Pharmacokinetics of coadministration of levothyroxine sodium and alendronate sodium new effervescent formulation

Osteoporos Int Pharmacokinetics of coadministration of levothyroxine sodium and alendronate sodium new effervescent formulation H. G. Bone 0 1 2 3 M. A. Walter 0 1 2 3 M. E. Hurley 0 1 2 3 S. Epstein 0 1 2 3 0 Hurley Consulting Associates Ltd. , 25 DeForest Avenue, Summit, NJ 07901 , USA 1 Mission Pharmacal Company , 10999 Interstate Highway 10 West, Suite 1000, San Antonio, TX 78230 , USA 2 Michigan Bone & Mineral Clinic , 22201 Moross Road, Suite 260, Detroit, MI 48236 , USA 3 Division of Endocrinology Diabetes and Bone Disease, Icahn School of Medicine at Mt. Sinai , Atran Building, 1428 Madison Avenue, 4th Floor, Box 1055, New York, NY 10029 , USA Summary No clinically important pharmacokinetic interference of alendronate occurred between a new effervescent formulation of alendronate and levothyroxine when coadministered. The combination does not materially affect levothyroxine absorption. Introduction Concurrent treatment of osteoporosis with alendronate (Aln) and hypothyroidism with levothyroxine (LT4) may be problematic because both drugs are to be taken separately after fasting overnight. The primary objective was to assess pharmacokinetic interactions between a new effervescent formulation of Aln (Aln-NEF) and LT4. Methods A randomized, open-label, 3-way crossover study was conducted in 30 healthy adults (15 women). Subjects were dosed 3 times, separated by 35 days, after overnight fasts, with Aln-NEF alone (70 mg), LT4 alone (600 μg), or Aln-NEF and LT4 concurrently. Samples were analyzed for plasma Aln and serum LT4. Pharmacokinetic drug-drug interaction was assessed using 90% confidence intervals (CIs) for the test/reference ratio of the geometric means for area under the concentration-time curve from time zero to last measureable time point (AUC0-t) and maximum concentration (Cmax). Results were compared to the default no-effect boundaries of 80 to 125% for the ratio Aln-NEF and LT4 concurrently/Aln-NEF alone and the ratio Aln-NEF and LT4 concurrently/LT4 alone. Results Geometric mean ratios (Aln-NEF with LT4/Aln-NEF alone) were 0.927 (90% CI 0.795-1.081) for AUC0-8 and 0.912 (90% CI 0.773-1.077) for Cmax, demonstrating LT4 does not appreciably affect the pharmacokinetics of Aln. Geometric mean ratios (LT4 with Aln-NEF/LT4 alone) were 1.049 (90% CI 0.983-1.119) for AUC0-48 and 1.075 (90% CI 1.006-1.148) for Cmax, demonstrating LT4 is bioequivalent between the 2 treatments. Coadministration of Aln-NEF and LT4 was well tolerated. Conclusions There was no clinically important pharmacokinetic interference between the Aln-NEF formulation and LT4. Aln-NEF does not materially affect LT4 absorption. Alendronate; Bisphosphonate; Drug interaction; Levothyroxine; Pharmacokinetics Introduction Alendronate (Aln) is a widely used bisphosphonate for treatment of osteoporosis in postmenopausal women and for treatment to increase bone mass in men with osteoporosis [ 1, 2 ]. A recently approved new effervescent formulation of Aln (AlnNEF) is given once weekly. As with all Aln formulations, AlnNEF must be taken after an overnight fast at least 30 min before the first food, beverage, or medication of the day because food decreases the absorption. The dosing instructions for Aln-NEF must be followed in order to assure adequate drug absorption and to minimize the risk of esophageal adverse reactions [3]. It may be challenging for a patient to take more than 1 prescribed medication in the fasted state. A search was performed to identify oral drugs taken in the fasted state [ 4 ]. The search identified six drugs that are to be taken exclusively under overnight fasting conditions: three bisphosphonates (Aln alone and in combination with cholecalciferol, ibandronate, and risedronate), levothyroxine (LT4), and linaclotide (a guanylate cyclase-C agonist used to treat chronic constipation). Many patients treated for osteoporosis may require thyroid hormone replacement. A study conducted in older adults (57 to 85 years of age) to estimate potential major drug-drug interactions of medications and supplements using a household interview documented the use of these medications [ 5 ]. Aln and LT4 were the 15th and 4th most commonly used drugs, respectively. It was estimated that 4.5% of older adults in the USA take Aln and 12.4% take LT4 [ 5 ]. Pharmacokinetics According to the approved product labeling, Aln has low oral bioavailability, and there is a well-documented decrease in its absorption when taken with food [ 3 ]. Clinical studies with Aln oral tablets (Fosamax®) showed the mean oral bioavailability relative to intravenous administration of Aln in women was 0.64% (for doses ranging from 5 to 70 mg) and 0.59% (for a dose of 10 mg) in men when administered after an overnight fast and 2 h before breakfast [ 3 ]. Aln was effective when administered at least 30 min before breakfast in studies of the treatment and prevention of osteoporosis [ 3 ]. Aln administration with coffee or orange juice reduced (...truncated)


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H. G. Bone, M. A. Walter, M. E. Hurley, S. Epstein. Pharmacokinetics of coadministration of levothyroxine sodium and alendronate sodium new effervescent formulation, Osteoporosis International, 2017, pp. 1745-1752, Volume 28, Issue 5, DOI: 10.1007/s00198-017-3941-3