Ibuprofen sodium is absorbed faster than standard Ibuprofen tablets: results of two open-label, randomized, crossover pharmacokinetic studies.

BACKGROUND: A novel ibuprofen (IBU) formulation, Advil(®) Film-Coated Tablets (IBUNa), was developed. OBJECTIVE: Pharmacokinetic comparison of IBUNa versus other IBU formulations. STUDY DESIGN: Two randomized, single-dose, open-label, five-way crossover pharmacokinetic studies. SETTING: Inpatient research clinic. SUBJECTS: Seventy-one healthy adult volunteers. INTERVENTION: Study 1: In three periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) Liqui-Gels(®) (IBULG) 2 × 200 mg, and Motrin(®) IB (IBUMot) 2 × 200 mg tablets. In two periods following a high-fat breakfast, subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg and IBULG 2 × 200 mg. Study 2: In five study periods, fasted subjects received 400-mg IBU dose equivalents as IBUNa 2 × 256 mg, Advil(®) FastGel(®) (IBUFG) 2 × 200 mg, Nurofen(®) (IBUNur) 2 × 200 mg, Advil(®) (IBUAdv) 2 × 200 mg, and Nurofen(®) Express containing IBU lysinate (IBULys) 2 × 342 mg. MAIN OUTCOME MEASURE: Log-transformed area under the plasma concentration versus time curve to last observable concentration (AUCL) and maximum plasma concentration (C max) were the primary pharmacokinetic parameters; time to maximum measured plasma concentration (T max) was analyzed post hoc. RESULTS: IBUNa was bioequivalent to IBULG (fasted and fed) and IBUFG and IBULys (fasted) for rate (C max) and extent (AUCL) of IBU absorption. After fasting, AUCL was bioequivalent for IBUNa and IBUMot, IBUAdv, and IBUNur, but C max occurred significantly earlier with IBUNa. After fasting, median IBUNa T max was comparable to that for IBULG, IBUFG, and IBULys, but was much shorter than that for IBUMot, IBUNur, and IBUAdv. Food slowed absorption of IBUNa and IBULG similarly. All treatments were tolerated similarly. CONCLUSION: IBUNa is absorbed faster but to a similar extent as standard IBU formulations.

Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants.

Alogliptin is a dipeptidyl peptidase-4 inhibitor under investigation for treatment of patients with type 2 diabetes mellitus. Potential pharmacokinetic (PK) drug-drug interactions of alogliptin with pioglitazone or glyburide were evaluated in healthy adults. In a randomized, 6-sequence, 3-period crossover study (study I), participants (n = 30 enrolled; n = 27 completed) received monotherapy with pioglitazone 45 mg once daily (qd), alogliptin 25 mg qd, or coadministration of the 2 agents. The 12-day treatment periods were separated by a > or =10-day washout interval. In a nonrandomized, single-sequence study (study II), participants (n = 24 completed) received a single 5-mg dose of the sulfonylurea glyburide, alone and after 8 days of dosing with alogliptin 25 mg qd. Sequential samples of blood (both studies) and urine (first study) were obtained for determination of PK parameters for alogliptin, pioglitazone, their metabolites, and glyburide. Minor changes in PK parameters between combination therapy and monotherapy were obtained but not judged to be clinically relevant. The combination treatments were well tolerated, although glyburide frequently caused hypoglycemia. Most adverse events were of mild intensity and occurred with a frequency similar to that with monotherapy. It is concluded that pioglitazone or glyburide can be administered with alogliptin without dose adjustment to any component of the combination therapy.

Pharmacokinetics of ciclesonide and desisobutyryl ciclesonide after administration via aqueous nasal spray or hydrofluoroalkane nasal aerosol compared with orally inhaled ciclesonide: an open-label, single-dose, three-period crossover study in healthy volunteers.

BACKGROUND: Ciclesonide, an intranasal corticosteroid, is administered as a prodrug and is converted to the active metabolite, desisobutyryl ciclesonide, in the upper and lower airways. Previous studies have assessed systemic exposure with the ciclesonide hydrofluoroalkane metered dose inhaler (CIC HFA-MDI) and the ciclesonide aqueous nasal spray (CIC-AQ) formulations. However, systemic exposure with ciclesonide HFA nasal aerosol (CIC-HFA) developed for the treatment of allergic rhinitis has not been investigated. OBJECTIVE: This study compared the systemic exposure of ciclesonide and desisobutyryl ciclesonide after administration of ciclesonide formulated as an aqueous nasal spray, an HFA nasal aerosol, or as an orally inhaled HFA-MDI. METHODS: Healthy adults (aged 18-60 years) were randomly assigned in an open-label, singledose, 3-period crossover design to CIC-AQ 300 microg, CIC-HFA 300 microg, or CIC HFA-MDI 320 microg. Serum samples were collected before study drug administration and at 5, 15, and 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 18, 22, and 24 hours after dosing. The primary pharmacokinetic parameters were AUC(0-infinity) and C(max) of desisobutyryl ciclesonide. Adverse events were elicited by direct questioning of participants throughout the study. RESULTS: Thirty volunteers were randomly assigned. Most of the volunteers were male (63% [19/30]) and white (83% [25/30]); the mean age was 36 years and mean weight was 68 kg. Concentrations of desisobutyryl ciclesonide were quantifiable (lower limit of quantitation [LLOQ] = 10 ng/L) in the serum samples of only 5 volunteers (of 30) receiving CIC-AQ, and the highest C(max) value of desisobutyryl ciclesonide was 26.7 ng/L (mean C(max), 15.2 ng/L). The AUC(0-infinity) of desisobutyryl ciclesonide for CIC-AQ was below the LLOQ of the bioanalytic assay. Mean C(max) and AUC(0-infinity) of desisobutyryl ciclesonide were 59.1 ng/L and 397.5 ng . h/L, respectively, for CIC-HFA; and 586.2 ng/L and 2685.0 ng . h/L, respectively, for CIC HFA-MDI. Concentrations of the parent compound, ciclesonide, were below the LLOQ in serum samples after administration of CIC-AQ; they were detectable up to 2 hours after administration of CIC-HFA and up to 4 hours after administration of CIC HFA-MDI. Treatment-emergent adverse events occurred with a low frequency in all 3 treatment groups (30% [9/30] overall) and were mild in intensity as determined by the study investigator. CONCLUSIONS: In this study, compared with that of CIC HFA-MDI, the systemic exposure of desisobutyryl ciclesonide was 10-fold lower after administration of CIC-HFA and at least 40-fold lower after administration of CIC-AQ. All treatments were well tolerated.

The absolute oral bioavailability and population-based pharmacokinetic modelling of a novel dipeptidylpeptidase-IV inhibitor, vildagliptin, in healthy volunteers.

BACKGROUND AND OBJECTIVE: Vildagliptin is a potent, selective, orally active inhibitor of dipeptidylpeptidase-IV being developed for the treatment of type 2 diabetes mellitus. The objective of this study was to assess the absolute oral bioavailability of vildagliptin by comparing the systemic exposure after oral and intravenous administration in healthy volunteers. METHODS: This was an open-label, randomised, two-period, two-treatment, crossover study in 11 healthy volunteers. Subjects received vildagliptin 50mg orally or 25mg as a 30-minute intravenous infusion on two occasions separated by a 72-hour washout period. Vildagliptin concentrations were determined by a specific assay in urine (lower limit of quantification [LLQ] = 5 ng/mL) and serial plasma samples (LLQ = 2 ng/mL) obtained up to 24 hours after dosing. Noncompartmental analysis and population pharmacokinetic modelling were performed. RESULTS: Both noncompartmental analysis and population pharmacokinetic modelling estimated the absolute oral bioavailability of vildagliptin to be 85%. Renal elimination of unchanged vildagliptin accounted for 33% and 21% of the administered dose 24 hours after intravenous and oral administration, respectively. Renal clearance (13 L/h) was approximately one-third of the total systemic clearance (41 L/h). Two peaks were observed in plasma concentrations at 1 and 3 hours after oral administration in nine of 11 subjects. Modelling based on the population approach identified two absorption sites with lag-times of 0.225 and 2.46 hours. Both absorption rate constants were slower than the elimination rate constant, indicating 'flip-flop' kinetics after oral administration. Bodyweight was identified as a factor with an impact on the volume of distribution of the peripheral compartment. Clearance was 24% greater in males (44.6 L/h) than in females (36.1 L/h). CONCLUSIONS: Vildagliptin is rapidly and well absorbed with an estimated absolute bioavailability of 85%. Two possible sites of absorption were identified, and the absorption rates were slower than the elimination rate, indicating a flip-flop phenomenon after oral dosing.

Replicate study design in bioequivalency assessment, pros and cons: bioavailabilities of the antidiabetic drugs pioglitazone and glimepiride present in a fixed-dose combination formulation.

An open-label, randomized, 2-sequence, 4-period crossover (7-day washout period between treatment), replicate design study was conducted in 37 healthy subjects to assess intersubject and intrasubject variabilities in the peak (Cmax) and total (AUC) exposures to 2 oral antidiabetic drugs, pioglitazone and glimepiride, after single doses of 30 mg pioglitazone and 4 mg glimepiride, given under fasted state, as commercial tablets coadministered or as a single fixed-dose combination tablet. Variabilities for AUC(infinity) for coadministered and fixed-dose combination treatments were similar: 16% to 19% (intra) and 23% to 25% (inter) for pioglitazone and 18% to 19% (intra) and 29% to 30% for glimepiride (inter, excluding 1 poor metabolizer). Fixed-dose combination/coadministered least squares mean ratios of >or=0.86 and the 90% confidence intervals of these ratios for pioglitazone and glimepiride of between 0.80 and 1.25 for Cmax, AUC(lqc), and AUC(infinity) met the bioequivalency standards. Gender analysis showed that women showed mean of 16% and 30% higher exposure than men for glimepiride (excluding 1 poor metabolizer) and pioglitazone, respectively. There was considerable overlapping in the AUC(infinity) values, making gender-dependent dosing unnecessary. Patients taking pioglitazone and glimepiride as cotherapy may replace their medication with a single fixed-dose combination tablet containing these 2 oral antidiabetic drugs.

Oral antidiabetic drugs: effect of food on absorption of pioglitazone and metformin from a fixed-dose combination tablet.

An open-label, randomized, crossover study involving 28 healthy subjects was conducted to compare the peak (Cmax) and total (AUC(lqc), AUC(infinity)) exposures to pioglitazone and metformin after single-dose administration of a fixed-dose combination tablet containing 15 mg of pioglitazone plus 850 mg metformin when given under fasted versus fed states, with a washout period of 7 days between treatments. Two different fixed-dose combination formulations (bilayer and pioglitazone-micronized fixed-dose combination tablets) were tested. The pioglitazone-micronized fixed-dose combination formulation was selected for clinical development and regulatory approval; the present study describes food effect results with this formulation. For pioglitazone, least squares mean ratios (fed/fasted) and the 90% confidence intervals of these ratios were 1.05 (0.93-1.18) for Cmax, 1.13 (1.02-1.25) for AUC(lqc), and 1.11 (1.01-1.22) for AUC(infinity). For metformin, these values were 0.72 (0.65-0.79) for Cmax, 0.87 (0.81-0.94) for AUC(lqc), and 0.87 (0.81-0.94) for AUC(infinity). Dosing with food resulted in median prolongation of tmax values by 1.5 hours for metformin and 2.0 hours for pioglitazone. Because bioequivalency criteria were met (fed/fasted 90% confidence interval between 0.80 and 1.25) for both pioglitazone and metformin AUC, fixed-dose combination tablets can be taken with or without food, but to minimize gastrointestinal adverse effects of metformin, the fixed-dose combination tablets are recommended to be taken with food.

Oral antidiabetic drugs: bioavailability assessment of fixed-dose combination tablets of pioglitazone and metformin. Effect of body weight, gender, and race on systemic exposures of each drug.

Bioavailability of pioglitazone and metformin, in 2 dose strengths, given either as a fixed-dose combination tablet or as coadministration of commercial tablets (coad), was studied in young healthy subjects in 2 separate studies. In study I (n = 63), single oral doses of 15-mg pioglitazone/500-mg metformin fixed-dose combination tablets or equivalent doses of commercial tablets were administered, in a fasting state, in an open-label, randomized, crossover study with a 7-day washout period between treatments. Study II (n = 61) was similar in design to study I, except the 15/850-mg fixed-dose combination tablet and coad treatments were evaluated. Least squares mean (fixed-dose combination/coad) ratios and 90% confidence intervals of the ratios for the 15/500-mg dose strength for the maximum observed serum concentration (Cmax) and area under the serum concentration-time curve from time 0 to infinity (AUC(infinity)) were 0.95 (0.86-1.05) and 1.02 (0.98-1.08), respectively, for pioglitazone and 0.99 (0.95-1.03) and 1.03 (0.98-1.08), respectively, for metformin. Bioequivalency for pioglitazone and metformin between fixed-dose combination tablets and coad treatments was met for both strengths of fixed-dose combination tablets. In a post hoc meta-analysis of combined data from the 2 studies (n = 124), there was considerable overlapping in AUC(infinity) values between gender and race (Caucasians, Blacks, and Hispanics), making neither gender- nor racial-based dosing of pioglitazone or metformin necessary.

Lumiracoxib: pharmacokinetic and pharmacodynamic profile when coadministered with fluconazole in healthy subjects.

This two-way crossover study evaluated the effect of fluconazole on the pharmacokinetics and selective COX-2 inhibition of lumiracoxib. Thirteen healthy subjects were randomized to fluconazole (day 1: 400 mg; days 2-4: 200 mg) or no drug. On day 4, all subjects received a single dose of lumiracoxib (400 mg). Lumiracoxib pharmacokinetics were assessed during the following 48 hours. Thromboxane B(2) (TxB(2)) inhibition was measured prior to lumiracoxib dosing and 2 hours afterwards. Fluconazole caused a small (18%) but not clinically relevant increase in lumiracoxib mean AUC(0- infinity ) but had no effect on lumiracoxib mean C(max). The geometric mean ratio (lumiracoxib plus fluconazole/lumiracoxib alone) for AUC(0- infinity ) was 1.19 (90% confidence interval [CI] = 1.12, 1.27) and for C(max) was 1.11 (90% CI = 0.98, 1.27). The decrease in TxB(2) from predose was not significantly different for lumiracoxib (11.8%) or lumiracoxib plus fluconazole (7.1%); no correlation between lumiracoxib concentration and TxB(2) decrease was seen. As fluconazole is a strong inhibitor of cytochrome P450 (CYP) 2C9, other CYP2C9 inhibitors are unlikely to affect lumiracoxib pharmacokinetics with clinical relevance, making dosage adjustment unnecessary.

Pharmacokinetics of histamine dihydrochloride in healthy volunteers and cancer patients: implications for combined immunotherapy with interleukin-2.

Recent clinical trials in melanoma and leukemia have demonstrated potential for increased survival time and improved remission when histamine dihydrochloride is added to cytokine monotherapy. In the present study, the pharmacokinetics of subcutaneous histamine (1 mg) in 21 healthy subjects and 12 melanoma patients was determined via model-dependent methods. Drug-drug interactions with subcutaneous interleukin-2 (1.1 mg) were evaluated in a combined cohort of patients with melanoma (n = 8) or renal cell carcinoma (n = 4). Histamine dihydrochloride administered over 10 minutes in healthy subjects peaked at 18 minutes (Cmax 38 nmol/L), attained a distribution volume of 59 L, and was eliminated at 6%/min. The results were similar in a 20-minute infusion in melanoma patients. No gender effects were observed (p > 0.05). Interleukin-2 injected either 10 minutes prior to or 10 minutes following histamine dihydrochloride had no effect on histamine kinetics. Histamine dihydrochloride administered 10 minutes prior to injection of interleukin-2 also had no effect on interleukin-2 kinetics. Maximal concentration of interleukin-2 (2,442 pg/ml) occurred at 2.5 hours with an elimination half-life of 1.7 hours, area under the curve (AUC) of 15,746 pg x h/ml, and volume of distribution and plasma clearance of 194 L and 74 L/h, respectively. However, interleukin-2 Cmax (1,758 pg/ml) and AUC (12,448 pg x h/ml) were reduced when histamine dihydrochloride was infused 10 minutes following interleukin-2, likely due to the pharmacodynamic effects of histamine, including increased heart rate and reduced blood pressure. It is concluded that histamine dihydrochloride and interleukin-2 can be safely coadministered with minimal interaction.