Arturo G. Porras

Characterization of rofecoxib as a cyclooxygenase‐2 isoform inhibitor and demonstration of analgesia in the dental pain model

Nonsteroidal anti‐inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin (INN, indometacin) inhibit both the constitutive (COX‐1) and inducible (COX‐2) isoforms of cyclooxygenase. The induction of COX‐2 after inflammatory stimuli has led to the hypothesis that COX‐2 inhibition primarily accounts for the therapeutic properties of NSAIDs.

Studies of the oral bioavailability of alendronate

Clinical studies were performed to examine the oral bioavailability of alendronate (4‐amino‐1‐hydroxybutylidene‐1,1‐bisphosphonate monosodium). All studies, with the exception of one performed in men, involved postmenopausal women. Short‐term (24 to 36 hours) urinary recovery of alendronate after an intravenous dose of 125 to 250 μg averaged about 40% in both men and women. In women, oral bioavailability of alendronate was independent of dose (5 to 80 mg) and averaged (90% confidence interval) 0.76% (0.58, 0.98) when taken with water in the fasting state, followed by a meal 2 hours later. Bioavailability was similar in men [0.59%, (0.43, 0.81)]. Taking alendronate either 60 or 30 minutes before a standardized breakfast reduced bioavailability by 40% relative to the 2‐hour wait. Taking alendronate either concurrently with or 2 hours after breakfast drastically (>85%) impaired availability. Black coffee or orange juice alone, when taken with the drug, also reduced bioavailability (approximately 60%). Increasing gastric pH, by infusion of ranitidine, was associated with a doubling of alendronate bioavailability. A practical dosing recommendation, derived from these findings and reflective of the long‐term nature of therapy for a disease such as osteoporosis, is that patients take the drug with water after an overnight fast and at least 30 minutes before any other food or beverage.

Elimination and Biochemical Responses to Intravenous Alendronate in Postmenopausal Osteoporosis

Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half‐life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half‐life of greater than 10 years (n = 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1 year.

Pharmacokinetics of Alendronate

Alendronate (alendronic acid; 4-amino-1-hydroxybutylidene bisphosphonate) has demonstrated effectiveness orally in the treatment and prevention of postmenopausal osteoporosis, corticosteroid-induced osteoporosis and Paget’s disease of the bone. Its primary mechanism of action involves the inhibition of osteoclastic bone resorption. The pharmacokinetics and pharmacodynamics of alendronate must be interpreted in the context of its unique properties, which include targeting to the skeleton and incorporation into the skeletal matrix.Preclinically, alendronate is not metabolised in animals and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although soon after administration the drug distributes widely in the body, this transient state is rapidly followed by a nonsaturable redistribution to skeletal tissues. Oral bioavailability is about 0.9 to 1.8%, and food markedly inhibits oral absorption. Removal of the drug from bone reflects the underlying rate of turnover of the skeleton. Renal clearance appears to involve both glomerular filtration and a specialised secretory pathway.Clinically, the pharmacokinetics of alendronate have been characterised almost exclusively based on urinary excretion data because of the extremely low concentrations achieved after oral administration. After intravenous administration of radiolabelled alendronate to women, no metabolites of the drug were detectable and urinary excretion was the sole means of elimination. About 40 to 60% of the dose is retained for a long time in the body, presumably in the skeleton, with no evidence of saturation or influence of one intravenous dose on the pharmacokinetics of subsequent doses.The oral bioavailability of alendronate in the fasted state is about 0.7%, with no significant difference between men and women. Absorption and disposition appear independent of dose. Food substantially reduces the bioavailability of oral alendronate; otherwise, no substantive drug interactions have been identified.The pharmacokinetic properties of alendronate are evident pharmacodynamically. Alendronate treatment results in an early and dose-dependent inhibition of skeletal resorption, which can be followed clinically with biochemical markers, and which ultimately reaches a plateau and is slowly reversible upon discontinuation of the drug. These findings reflect the uptake of the drug into bone, where it exerts its pharmacological activity, and a time course that results from the long residence time in the skeleton. The net result is that alendronate corrects the underlying imbalance in skeletal turnover characteristic of several disease states. In women with postmenopausal osteoporosis, for example, alendronate treatment results in increases in bone mass and a reduction in fracture incidence, including at the hip.

Pharmacokinetics, COX-2 specificity, and tolerability of supratherapeutic doses of rofecoxib in humans.

AbstractObjective: Prostaglandin synthesis is catalyzed by a constitutive cyclo-oxygenase isoform (COX-1) and an inducible isoform (COX-2). It is hypothesized that the analgesic and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (nonspecific COX-1/COX-2 inhibitors) such as ibuprofen principally derive from COX-2 inhibition. The purpose of this study was to evaluate steady-state pharmacokinetics, biochemical selectivity and tolerability of rofecoxib (VioxxTM), characterized in vitro as a COX-2 inhibitor.nn Methods: Four panels of healthy men (n=8 per panel) were administered rofecoxib (n=6) (25, 100, 250, 375u2009mg) or placebo (n=2) once daily on dayu20091 and daysu20093–14. Blood samples for assays of rofecoxib plasma concentration and COX isoform activity were obtained pre-dose and at specified time points post-dose.nn Results: Rofecoxib pharmacokinetics were found to be complex and nonlinear. Elimination half-life ranged from 9.9u2009h to 17.5u2009h after multiple dosing with an accumulation ratio close to 2 for all doses. COX-2 inhibitory activity as assessed by average inhibition of whole blood lipopolysaccharide-stimulated prostaglandin E2 over the 8-h post-dose period on dayu200914 was 0.3, 67, 96, 92 and 96% for the placebo and the 25-, 100-, 250- and 375-mg treatment groups, respectively. No treatment group showed significant inhibition of COX-1 as assessed by thromboxane B2 generation in clotting whole blood. Side effects were mild and transient.nn Conclusion: The results indicate that rofecoxib is a potent and specific inhibitor of COX-2 in humans even at doses more than tenfold higher than those associated with efficacy in patients with osteoarthritis.

The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin

The objective of this study was to examine the effect of 3 doses of rofecoxib (12.5, 25, and 50 mg) on the pharmacodynamics and pharmacokinetics of warfarin.

Pharmacokinetic considerations in determining the terminal elimination half-lives of bisphosphonates.

AbstractBackground and objective: Bisphosphonates are commonly used to treat and prevent osteoporosis. These compounds have unusual pharmacokinetic characteristics because they bind strongly to bone, and a portion becomes buried under newly formed bone. Once incorporated into bone tissue, the subsequent release during bone remodeling is probably the rate-limiting step in the terminal elimination of bisphosphonates. Because of this unique property of bisphosphonates, pharmacokinetic studies with insufficient lengths of follow-up might entirely miss the true terminal elimination phase. A terminal half-life (t1/2γ) of approximately 11 years, similar to that of calcium and other minerals in bone, was reported from an 18-month study of alendronic acid in postmenopausal women with osteoporosis. We are not aware of any other published reports in which the elimination of a bisphosphonate has been followed for more than a few weeks post-dose. The purpose of the present study was to reanalyse the alendronic acid data to examine the effect of truncating the length of follow-up on the calculated t1/2γ.n Patients and methods: Twenty-one postmenopausal women with osteoporosis (mean age 66 years) received intravenous alendronic acid 30mg over 4 consecutive days (7.5 mg/day), and urinary excretion of alendronic acid was monitored over the following 18–24 months. Terminal elimination half-life was originally calculated by log-linear regression of the percentage retained versus time curve between days 240 and 540 and substituting the slope of the regression line into the equation, t1/2γ = −log 2/slope. These data were reanalysed based on the period up to 30 days.n Results: Data were sufficient for analysis of pharmacokinetics in 11 patients. A mean t1/2γ of approximately 11 years was reported previously, based on analysis of data between days 240 and 540. Recalculating the ‘terminal’ half-life of alendronic acid using only data from the first 30 days resulted in an ‘observed’ half-life of only 11 days.n Conclusion: This analysis illustrates the importance of sufficient length of follow-up to accurately characterise the true terminal elimination half-life of bisphosphonates. The relatively short (expressed in units of days rather than years) terminal elimination half-lives reported for some bisphosphonates based on only 30 days of follow-up or less are likely to substantially underestimate the true terminal elimination half-lives.

Bioavailability of Alendronate and Vitamin D3 in an Alendronate/Vitamin D3 Combination Tablet

These studies were designed to demonstrate that the alendronate (ALN) component of an ALN/vitamin D3 combination tablet was bioequivalent to the 70‐mg ALN tablet and that the pharmacokinetic parameters of vitamin D3 were similar with or without ALN. These were open‐label, randomized, 2‐part, 2‐period, crossover studies. In part I, participants received either a single combination tablet or ALN 70 mg. In part II, participants received either a single combination tablet or vitamin D3 alone. Results from part I showed that the geometric mean ratio (GMR) for total urinary excretion of ALN for both studies fell within the prespecified bioequivalence bounds. Results from part II showed that the pharmacokinetic profiles of vitamin D3 with or without ALN were also similar. The combination tablets are bioequivalent to the ALN 70‐mg tablet with respect to ALN bioavailability. The bioavailability of vitamin D3 is similar in the combination tablets and when administered alone. No serious adverse experiences were reported.

Bioavailability and Short-Term Tolerability of Alendronate in Glucocorticoid-Treated Children

BACKGROUNDnChildren receiving glucocorticoids (GCs) are at an increased risk of fragility fractures. Conservative measures may be inadequate in treating low bone mass, giving rise to fractures in this population; as such, attention has turned to the use of bisphosphonates.nnnOBJECTIVEnThe goal of this study was to evaluate the bioavailability and single-dose tolerability of alendronate (ALN) in children receiving a stable dose of GCs.nnnMETHODSnChildren (ages 4-17 years) receiving GC treatment for their chronic illnesses received intravenous (125 μg) and oral (35 mg) ALN in a 2-period, randomized crossover study, with doses separated by at least a 7-day washout period. Urine was collected for either 8 or 24 hours after drug administration to determine urinary excretion of ALN and bioavailability. Tolerability was assessed by continuous collection of adverse events reported during the study. The main outcome measures were total urinary excretion rates, oral bioavailability of ALN, and adverse events.nnnRESULTSnThere were 12 patients in the 4- to 11-year-old group (mean age, 8.1 years; 5 girls) and 12 patients in the 12- to 17-year-old group (mean age, 14.3 years; 5 girls). The least-squares mean bioavailability (90% CI) for children aged 4 to 11 years (n = 12) was 0.43% (0.27-0.67) and for children aged 12 to 17 years (n = 12) it was 0.39% (0.26-0.60). The least-squares mean bioavailability for all ages combined was 0.41% (0.30-0.56), with no statistical difference between the 2 age groups. The total urinary excretion of ALN after the intravenous dose was similar between groups. Fifteen patients reported a total of 36 transient clinical nonserious adverse events, all of which were mild or moderate in intensity; the most common were headache (n = 13), abdominal pain (n = 3), limb, neck, or facial pain (n = 6), and ankle or knee swelling (n = 3).nnnCONCLUSIONSnThe mean oral bioavailability of ALN was similar to previous pharmacokinetic studies in children with osteogenesis imperfecta and slightly lower than that observed in historical adult controls. Alendronate was generally well tolerated, with minor adverse events that resolved uneventfully. Elucidation of the full adverse-effect profile of this agent was limited by the single-dose nature of this study, and robust comparisons of the pharmacokinetics of ALN in different age groups may need a larger number of patients.

Effects of renal insufficiency and hemodialysis on the pharmacokinetics of rofecoxib.

Rofecoxib (VIOXX™, Merck & Co., West Point, PA) is a COX-2–selective inhibitor that combines anti-inflammatory and analgesic efficacy with improved gastrointestinal (GI) safety. The present open-label study investigated the pharmacokinetics, safety, and tolerability of a single, oral dose of rofecoxib (50 mg) in patients with end-stage renal failure (creatinine clearance <5 mL/min/1.73 m2) requiring hemodialysis. Rofecoxib AUC(0–48 h), AUC(0–∞), Cmax, Tmax, and t1/2 obtained from renal failure patients on hemodialysis were not significantly different from those obtained from healthy subjects. With hemodialysis initiated 48 hours postdose, rofecoxib AUC(0–48 h) adjusted mean ratio (renal failure/healthy subjects) was 0.81, with a corresponding 90% confidence interval (CI; 0.66, 1.00). Hemodialysis per se had no clinically meaningful effect on rofecoxib pharmacokinetics: plasma rofecoxib concentration-time curves were virtually superimposable when hemodialysis was initiated at 4 or 48 hours following rofecoxib dosing, although mean rofecoxib Cmax was 18% lower during the former (325 versus 395 ng/mL; P = 0.014). Overall, rofecoxib was well tolerated in end-stage renal disease patients. In this study, end-stage renal disease and hemodialysis had little effect on rofecoxib pharmacokinetics. Although there are no clinical data to support the use of rofecoxib in patients with severe renal insufficiency (creatinine clearance, 5–30 mL/min/1.73 m2), these data suggest that dosage adjustment of rofecoxib is not needed for patients with impaired renal function.