Standard High-fat Breakfast Research Articles

Abstract C071: Pharmacokinetics and pharmacodynamics of pemigatinib, a potent and selective inhibitor of FGFR 1, 2, and 3, in patients with advanced malignancies

Abstract Pemigatinib is a potent inhibitor of fibroblast growth factor receptors (FGFR) 1, 2, and 3 with selectivity against other kinases and is currently being studied in solid tumors expressing FGFR translocations and/or mutations. A first-in-man phase 1 study (FIGHT-101) was conducted in patients with solid tumors who are refractory to approved treatments, to establish the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of pemigatinib. The study was conducted in 3 parts to allow dose escalation, dose expansion, and food-effect and combination treatments, respectively. Both intermittent (2 wks on/1 wk off) and continuous daily dosing were evaluated. A total of 116 patients have received monotherapy and 44 received combination therapy, as of February 19, 2019. Serial blood samples were collected to enable PK/PD analyses, and plasma samples were assayed for pemigatinib by a validated LC-MS/MS method with a linear validated range of 1 to 1000 nM in human plasma. With multiple-dose administration in the fasted state, pemigatinib plasma concentrations attained peak values (Cmax) typically at 1–2 hours (median Tmax) post-dose, and subsequently exhibited a bi-exponential decay, with a steady-state geometric mean terminal-phase disposition half-life (t½) of approximately 15 hours that was not dose-dependent. The geometric mean accumulation ratio was approximately 1.6 for area under the curve from time 0 to 24 hours (AUC0-24). Within the dose range of 1 to 20 mg once daily (QD), increases in the pemigatinib steady-state Cmax and AUC0-24 were proportional to dose; that is, pemigatinib exhibited linear PK over the dose range studied. Pemigatinib exhibited a low steady-state oral clearance with geometric mean of 9.88–11.7 L/h and moderate volume of distribution with geometric mean of 173–244 L. At the recommended part 2 dose of 13.5 mg QD, the geometric mean (CV%) of t½, steady-state Cmax, and AUC0-24 were 15.4 h (51.6%), 236 nM (56.4%), and 2620 h*nM (54.1%), respectively. The PK parameters of pemigatinib following combination therapy were similar to that of monotherapy. Administration of a standardized high-fat and high-calorie breakfast prolonged the median pemigatinib Tmax to 4 hours, decreased the geometric mean steady-state Cmax by 18%, and increased the geometric mean steady-state AUC0-24 by 11%. The 90% CI of geometric mean ratio for steady-state Cmax and AUC0-24 were (0.648–1.03) and (0.935–1.31), respectively. The effect of food on pemigatinib plasma exposures was considered as modest and not clinically meaningful. Therefore, pemigatinib can be administered without regard to food. The geometric mean fraction of pemigatinib excreted in urine was 1.19% (range, 0.226–7.24%) with a geometric mean renal clearance of 0.133 L/h based on exploratory urine excretion data, indicating minor contribution from renal clearance towards total systemic clearance. Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition. The increase in serum phosphorus observed after treatment with pemigatinib was exposure-dependent and followed a sigmoidal relationship. In conclusion, pemigatinib exhibits rapid absorption, linear PK, and a t½ consistent with QD dosing. Pemigatinib is predominantly cleared by metabolism and there are no active metabolites. Citation Format: Tao Ji, Christine Lihou, Ekaterine Asatiani, Luis Féliz, Heather Overholt, Robert Landman, Xuejun Chen, Swamy Yeleswaram. Pharmacokinetics and pharmacodynamics of pemigatinib, a potent and selective inhibitor of FGFR 1, 2, and 3, in patients with advanced malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C071. doi:10.1158/1535-7163.TARG-19-C071

2229. Relative Bioavailability of a Single Oral Dose of SUBA-Itraconazole 65 mg Capsule Compared with Conventional Itraconazole 100 mg Capsule Administered Under Fasted and Fed Conditions in Healthy Adult Volunteers

BackgroundConventional itraconazole (CI) absorption from capsules even under fed conditions is suboptimal (~55%), let alone when fasted. SUBA-itraconazole (SI) is ~1.8x’s more bioavailable than CI at steady-state in a fed condition. There are, however, no data comparing these formulations under a fasted state. A single-dose PK study was performed comparing bioavailability of 65mg SI to 100mg CI under fasted or fed conditions.MethodsThis was an open-label, single-dose, randomized, four-period, four-treatment, four-sequence, crossover bioequivalence study under fasted and fed conditions in healthy adults. Subjects were administered a single dose of SI (1 × 65 mg) and CI (1 × 100 mg). Under fasted condition, subjects were administered SI or CI following an overnight fast of at least 10 hours. Subjects under fed condition were administered SI or CI after 30 minutes of consuming a standardized high fat breakfast preceded by an overnight fast of at least 10 hours. After dosing, all subjects fasted for at least 4 hours post-dose in all periods. Blood samples were collected prior to dosing and then from 1 to 120 hours. Analysis of itraconazole (IZ) and hydoxyitraconazole (HIZ) serum levels was by least-squares-geometric means of PK parameters.ResultsUnder fasted condition, Cmax and AUCtau of IZ for SI were substantially higher compared with CI (Table, Figure 1). Under fed conditions, however, the Cmax and AUCtau of IZ for SI was 20% and 10% lower, respectively (table, Figure 2). Similar results were found for HIZ. The Tmax for IZ and HIZ of SI and CI were similar under a fasted condition but extended by over 2 hours for SI vs. CI under fed conditions. Study drugs were well-tolerated under fasted and fed conditions. All TEAEs were mild and resolved at the end of the study. Fifty of 52 subjects enrolled completed the study. Two subjects did not complete the study due to not being able to finish a high fat meal and noncompliance. No SAEs were reported.ConclusionTotal and peak IZ/HIZ exposure was substantially higher for SI under fasted conditions compared with CI, but slightly lower under fed conditions with similar safety profiles. This study demonstrates the unique nature of the SI formulation compared with CI under fasted conditions and may lead to less variability if patients are not adherent to dietary requirements when taking itraconazole. Disclosures All authors: No reported disclosures.

A Randomised, Cross-Over Study to Estimate the Influence of Food on the 25-Hydroxyvitamin D₃ Serum Level after Vitamin D₃ Supplementation.

Vitamin D3 is known to be liposoluble and its release could be a factor limiting the rate of absorption. It was presumed that the presence of fat could favor absorption of vitamin D3. However, as bioavailability is related not only to the active molecules but also to the formulations and excipients used, the optimization of the pharmaceutical form of vitamin D3 is also important. The objective of this study was to evaluate if there is a food effect on absorption when a high dose of vitamin D3 is completely solubilized in an oily solution. In the present cross-over study, 88 subjects were randomized and received a single dose of 50,000 IU of vitamin D3 in fasting state or with a standardized high-fat breakfast. Assessment of serum concentrations of 25 hydroxyvitamin D3 (25(OH)D3) was performed three, five, seven, 14, 30 and 60 days after supplementation. In fed and fast conditions, the 25(OH)D3 serum concentrations were significantly higher than the baseline value three days after administration and remained significantly higher during the first month. No significant difference between fasting vs. fed conditions was observed. It is therefore concluded that the vitamin D3 absorption from an oily solution was not influenced by the presence or absence of a meal.

The Absence of a Clinically Significant Effect of Food on the Single Dose Pharmacokinetics of Vorapaxar, a PAR-1 Antagonist, in Healthy Adult Subjects.

In this open-label, randomized, 2-period crossover study, 16 healthy subjects received a single oral 2.5-mg dose of vorapaxar in the fed (i.e., standardized high-fat breakfast) and fasted (i.e., an overnight fast) state with a 6-week washout. Plasma samples for vorapaxar assay were obtained pre-dose and up to 72 hours post-dose. Least squares (LS) geometric mean AUC0-72 hr and Cmax were analyzed by ANOVA. If 90% confidence intervals (CI) for the geometric mean ratios (GMRs; fed/fasted) of AUC0-72 hr and Cmax were within the 50-200% range, then food was deemed not to have a clinically important effect. The LS geometric mean (90% CI) AUC0-72 hr and Cmax of vorapaxar in the fasted state were 314 (284-348) ng hr/mL and 23.4 (20.7-26.4) ng/mL, respectively. The GMRs (fed/fasted) and 90% CIs for AUC0-72 hr and Cmax were 96.9 (92.2-102) and 79.1 (67.6-92.5), respectively. Vorapaxar was generally safe and well tolerated in the presence and absence of food. Concomitant food decreased the rate (i.e., 21% reduction in Cmax and 45-min delay in Tmax ) with no effect on the extent of vorapaxar absorption when administered as a single 2.5-mg dose. Thus, vorapaxar can be administered without regard to food.

Acute appearance of fatty acids in human plasma – a comparative study between polar-lipid rich oil from the microalgae Nannochloropsis oculata and krill oil in healthy young males

BackgroundThe long-chain n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have human health benefits. Alternatives to fish as sources of EPA and DHA are needed. Oil from the micro-algae Nannochloropsis oculata contains a significant amount of EPA conjugated to phospholipids and glycolipids and no DHA. Krill oil contains EPA and DHA conjugated to phospholipids. We compare the appearance of fatty acids in blood plasma of healthy humans after consuming a high fat meal followed by either algal oil or krill oil.MethodsTen healthy males aged 18-45 years consumed a standard high fat (55 g) breakfast followed by either algal oil (providing 1.5 g EPA and no DHA) or krill oil (providing 1.02 g EPA and 0.54 g DHA). All participants consumed both oils in random order and separated by 7 days. Blood samples were collected before the breakfast and at several time points up to 10 hours after taking the oils. Fatty acid concentrations (μg/ml) in plasma were determined by gas chromatography.ResultsFatty acids derived mainly from the breakfast appeared rapidly in plasma, peaking about 3 hours after consuming the breakfast, and in a pattern that reflected their content in the breakfast. There were time-dependent increases in the concentrations of both EPA and DHA with both algal oil (P < 0.001 for EPA; P = 0.027 for DHA) and krill oil (P < 0.001 for both EPA and DHA). The concentration of EPA was higher with algal oil than with krill oil at several time points. DHA concentration did not differ between oils at any time point. The maximum concentration of EPA was higher with algal oil (P = 0.010) and both the area under the concentration curve (AUC) and the incremental AUC for EPA were greater with algal oil (P = 0.020 and 0.006). There was no difference between oils in the AUC or the incremental AUC for DHA.ConclusionThis study in healthy young men given a single dose of oil indicates that the polar-lipid rich oil from the algae Nannochloropis oculata is a good source of EPA in humans.

Abstract 752: The effect of food on the pharmacokinetics of tivozanib

Abstract Background: Tivozanib, a potent, selective, long-half-life tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, has demonstrated antitumor activity in a Phase II study in patients with renal cell carcinoma (RCC), and is currently being studied in clinical trials in patients with RCC and other solid tumors. The goal of this study was to investigate the effect of food on the pharmacokinetics (PK) of a single 1.5 mg dose of tivozanib in healthy subjects. Methods: This was a single-center, open-label, randomized, two-period, crossover Phase I trial. Subjects were admitted to the clinical research unit (CRU) 1 day before dosing, fasted ∼10 hours, and were randomized to fed (standard high-fat breakfast)/fasted or fasted/fed sequence. In each phase of the sequence, subjects received a single oral dose of tivozanib 1.5 mg with a 6-week washout period between doses. Subjects remained at the CRU for at least 48 hours post dose for blood sample collection and safety monitoring, and were assessed on an outpatient basis for up to 504 hours post dose. PK data were analyzed by non-compartmental methods. The effect of food on PK was assessed using standard criteria for bioequivalence based on the exposure parameters AUC0-α and Cmax. If the 90% confidence intervals for the fed/fasted AUC0-α and Cmax fell within the range of 80% to 125%, it was concluded that food had no effect on exposure. Results: Thirty healthy volunteers were enrolled (19M/11F; mean age 39 years [range 22-53 years]). There was no significant difference in AUC0-α of serum tivozanib between the fed and fasted states (107.4%; Table 1). Food caused a significant decrease in serum tivozanib levels vs fasted state (Cmax: 77.5%). Conclusions: These results indicate that dosing tivozanib with food decreases maximal concentrations by ∼ 23%, but does not affect overall exposure. As tivozanib is dosed chronically in oncology patients and accumulates ∼6 to 7 times single-dose levels when at steady-state, these results are not likely to affect dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 752. doi:1538-7445.AM2012-752

Pharmacokinetics of a New Once-Daily Controlled-Release Formulation of Aceclofenac in Korean Healthy Subjects Compared with Immediate-Release Aceclofenac and the Effect of Food

A new controlled-release formulation of aceclofenac 200 mg (Clanza CR®) developed by Korea United Pharm., Inc., South Korea, for once-daily (od) dosing provides biphasic aceclofenac release consisting of immediate release of 85 mg followed by sustained release of 115 mg. Food has been known to affect the rate and extent of absorption of several drugs, in both immediate-release and controlled-release formulations. The aim of this study was to evaluate the relative bioavailability of a new controlled-release formulation of aceclofenac (200 mg od; Clanza CR®) in comparison with immediate-release aceclofenac (100 mg twice daily [bid], Airtal®) and to assess the effect of food on the pharmacokinetics of the new controlled-release aceclofenac formulation. This study was designed as a randomized, open-label, three treatment-period, crossover, single-centre study with a 1-week washout in 41 healthy adults. The three treatments consisted of immediate-release aceclofenac 100 mg bid administered under fasting conditions; controlled-release aceclofenac 200 mg od administered under fasting conditions; and controlled-release aceclofenac 200 mg od administered immediately after a standardized high-fat breakfast. Plasma concentrations of aceclofenac were determined using a high-performance liquid chromatography method. In the fasted state, the 90% confidence intervals (CIs) of the least squares geometric mean ratios (GMRs) for the area under the plasma concentration-time curve from time zero to 24 hours (AUC(24)) and the peak plasma concentration (C(max)) of aceclofenac for the controlled-release and immediate-release formulations of aceclofenac were all within the bioequivalence criteria range of 0.8-1.25. The 90% CIs of the GMRs for the AUC(24) and C(max) of aceclofenac for the controlled-release formulation of aceclofenac in the fed and fasted states were also within the bioequivalence range. Both aceclofenac formulations were well tolerated in all subjects, and no serious adverse effects were observed. The results demonstrate that controlled-release aceclofenac 200 mg is equivalent to immediate-release aceclofenac 100 mg when administered at the same total daily dose. Additionally, the bioavailability of controlled-release aceclofenac was not affected by high-fat foods.

Effect of Food on Bioavailability of a Single Oral Dose of Clopidogrel in Healthy Male Subjects

The present study aimed at investigating the effects of concomitant food intake on the bioavailability of a single oral dose of clopidogrel (CAS 113665-84-2). Clopidogrel was given under two conditions separated by a 14-day washout period: fasted and fed (after a standardized high fat breakfast). Concentrations of clopidogrel in plasma were quantified by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) with positive ion electro-spray ionization using multiple reaction monitoring (MRM). Pharmacokinetic parameters such as Cmax, Tmax, AUC0-t, AUC0-inf and tl/2z were estimated using a noncompartmental model. The pharmacokinetic parameters were significantly affected by food intake. Specifically, Cm, and AUC0-inf of clopidogrel increased 6.1-fold and 9.2-fold, respectively, in the fed condition compared to the fasted condition. The t1/2 increased from 2.5 h in the fasted state to 5.0 h in the fed state. The limit of quantification was 5 pg/mL for plasma clopidogrel analysis. Food substantially enhanced the bioavallability of clopidogrel in healthy subjects.

The effect of food on the single dose pharmacokinetics of cediranib

14533 Background: Cediranib (AZD2171) is an oral, highly potent and selective inhibitor of vascular endothelial growth factor (VEGF) signaling, with activity against VEGFR-1, -2 and -3. The effect of food on the pharmacokinetic (PK) profile of cediranib is not known. This study compared the single dose exposure PK parameters of cediranib following single oral doses to patients after a) a standard regulatory meal and b) an overnight fast. Methods: In this randomized, open-label, two-period, crossover study, 34 patients with advanced solid tumors refractory to standard therapies, ECOG PS ≤2, with adequate hematologic, renal and liver function, received two single doses of cediranib 45 mg with ≥8 days washout period. Patients were randomized to receive treatment in either the fed then the fasted state (group 1) or the fasted then the fed state (group 2). In the fed period, patients ate a standard high-fat breakfast (as per FDA guidelines) prior to dosing with cediranib. In both groups, intensive PK sampling occurred over 168 hours post dosing on each occasion. The effect of food on the single dose PK of cediranib was assessed using the criteria for establishing bioequivalence based on the endpoints of AUC and Cmax. Food would be considered to have no effect on the PK of cediranib if confidence intervals (CI) for the food effect ratio for endpoints of AUC and Cmax fell within the acceptance range of 0.8–1.25. CI of 94% were used in order to allow for the 2-group sequential design of the study and obtain an overall 5% significance level. Results: Both the AUC and Cmax of cediranib were lower in the presence of food by a mean of 24% and 33% respectively (94% CI: AUC, 12–34% and Cmax, 20–43%; Table 1). The CI for AUC crossed the lower equivalence boundary of 0.8 but the entirety of the CI was <1. The CI for Cmax was entirely outside the equivalence boundary, indicating a clear food effect. Conclusions: These data indicate that food reduces cediranib plasma exposure in terms of AUC and Cmax. It is recommended that cediranib be administered at least 1 hour before or 2 hours after food. Table 1. 1. Results of primary analysis Fasted GLS mean Fed GLS mean Food effect ratio* 94% CI AUC (ng·h/mL) 2450 1870 0.762 (0.663, 0.876) Cmax (ng/mL) 130 87.3 0.672 (0.567, 0.796) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology AstraZeneca Oncology AstraZeneca Oncology AstraZeneca Oncology

Influence of Food Intake on the Pharmacokinetics of Miglustat, an Inhibitor of Glucosylceramide Synthase

The objective of this study was to investigate the effect of food on the pharmacokinetics of miglustat, an inhibitor of glucosylceramide synthase. Twenty-four healthy male (n = 9) and female (n = 15) subjects were treated in a randomized, 2-way crossover design with a single oral dose of 100 mg miglustat with or without food. Consumption of a standard high-fat breakfast within 30 minutes before administration of miglustat significantly reduced peak exposure but did not significantly affect the extent of systemic exposure to miglustat. The peak plasma concentration (C(max)) decreased by 36% on average following administration with food. Area under the plasma concentration-time curve (AUC(0-infinity)) showed a modest (14%) decrease with food, but the 90% confidence interval was within the acceptance limit of 80% to 125%. The median (min-max) time to C(max) (t(max)) was prolonged from 2.5 (1.0-4.0) hours in the fasted state to 4.5 (1.5-8.0) hours in the fed state, whereas the apparent terminal half-life was approximately 8 hours and not affected by food. In conclusion, the intake of food has an effect on some pharmacokinetic parameters such as C(max) and t(max) but does not affect the extent of exposure to miglustat. The observed effects of food intake on the pharmacokinetics of miglustat are not considered to be of clinical relevance.

Pharmacokinetics and Short-Term Safety of 873140, a Novel CCR5 Antagonist, in Healthy Adult Subjects

873140 is a novel CCR5 antagonist with potent in vitro anti-human immunodeficiency virus (HIV) activity. This study was a double-blind, randomized, placebo-controlled, single- and repeat-dose escalation investigation of the safety, pharmacokinetics, and food effect of 873140 in 70 adult subjects. During single-dose escalation, three cohorts (each composed of 10 subjects, with 8 subjects receiving the active drug and 2 subjects receiving the placebo [8 active and 2 placebo]) received doses of 50, 200, 400, 800, and 1,200 mg after an overnight fast, or 400 mg plus a standard high-fat breakfast in an alternating panel design. During repeat-dose escalation, four cohorts (each with 8 active and 2 placebo) received doses of 200, 400, 600, or 800 mg every 12 h (BID) for 8 days. Laboratory safety tests, vital signs, and electrocardiograms (ECGs) were performed at regular intervals, and blood samples were obtained for pharmacokinetics. Single and repeat doses of 50 mg to 800 mg were well tolerated, with no serious adverse events and no grade 3 or 4 adverse events. The mild-to-moderate side effects were primarily gastrointestinal and included abdominal cramping, nausea, and diarrhea. No specific trends in laboratory parameters or clinically significant ECG changes were noted. Plasma 873140 concentrations increased rapidly; the median time to maximum concentration of drug in serum was 1.75 to 5 h. The median area under the plasma concentration-time profile (AUC) and the maximum concentration of drug in serum (C(max)) ranged from 127 ng.h/ml and 24 ng/ml at 200 mg BID to 329 ng.h/ml and 100 ng/ml at 800 mg BID, respectively. Food consumption increased the AUC and C(max) by a mean of 1.7- and 2.2-fold, respectively. The pharmacokinetic and safety profile supports the continued investigation of 873140 with HIV-infected subjects.

Echinacea alkamide disposition and pharmacokinetics in humans after tablet ingestion

Echinacea is a widely used herbal remedy for the treatment of colds and other infections. However, almost nothing is known about the disposition and pharmacokinetics of any of its components, particularly the alkamides and caffeic acid conjugates which are thought to be the active phytochemicals. In this investigation, we have examined serial plasma samples from 9 healthy volunteers who ingested echinacea tablets manufactured from ethanolic liquid extracts of Echinacea angustifolia and Echinacea purpurea immediately after a standard high fat breakfast. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkamides were rapidly absorbed and were measurable in plasma 20 min after tablet ingestion and remained detectable for up to 12 h. Concentration–time curves for 2,4-diene and 2-ene alkamides were determined. The maximal concentrations for the sum of alkamides in human plasma were reached within 2.3 h post ingestion and averaged 336 ± 131 ng eq/mL plasma. No obvious differences were observed in the pharmacokinetics of individual or total alkamides in 2 additional fasted subjects who took the same dose of the echinacea preparation. This single dose study provides evidence that alkamides are orally available and that their pharmacokinetics are in agreement with the one dose three times daily regimen already recommended for echinacea.

Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects With Varying Degrees of Chronic Renal Disease

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C(max), CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.

Pharmacokinetic properties of combination oxycodone plus racemic ibuprofen: Two randomized, open-label, crossover studies in healthy adult volunteers

Background: As part of ongoing studies to evaluate the analgesic efficacy and pharmacokinetic properties of combination oxycodone plus ibuprofen in the treatment of moderate to severe acute pain, 2 pharmacokinetic studies were conducted. Objectives: The goals of these studies were to compare the pharmacokinetic properties of monotherapy with oxycodone or ibuprofen with those of a tablet formulation of these 2 agents combined (study A), and to determine whether the absorption of the individual agents when given in the combination tablet was affected by the concomitant ingestion of food (study B). Methods: Study A was a single-center, open-label, randomized, single-dose, 3-period, 3-way, crossover study Healthy male subjects received oxycodone 5 mg, ibuprofen 400 mg, or a combination tablet containing both, after an overnight fast of ≥8 hours, on study days 1, 8, and 15. Study B was a single-center, open-label, randomized, single-dose, single-crossover study. Healthy volunteers received a tablet containing a combination of oxycodone 5 mg plus ibuprofen 400 mg after either an overnight fast of ≥8 hours or a standardized high-fat breakfast. Both studies included a washout period of ≥7 days between treatments. In both studies, the pharmacokinetic properties (C max, T max, t 1/2, AUC 0-4, AUC 0-1, and AUC 0-∞) of oxycodone and ibuprofen were derived from plasma drug concentrations. Analysis of variance was used to determine and compare pharmacokinetic properties. Results: Twenty-four healthy, white, male subjects were included in study A (mean age, 26.0 years; mean body weight, 71.3 kg; mean height, 170.0 cm). Study B involved 12 subjects (11 men, 1 woman; mean age, 24.8 years; mean body weight, 77.2 kg; mean height, 181.4 cm). The pharmacokinetic properties of ibuprofen and oxycodone were not statistically different when administered alone or combined. Food intake did not affect the rate of oxycodone absorption (90% Cl of C max of fasted state vs fed state, 103–130), or the rate (90% Cl of C max of fasted state vs fed state, 72–95) or extent (90% Cl of AUC 0-∞ of fasted state vs fed state, 88–102) of ibuprofen absorption. The extent of oxycodone absorption was slightly increased when the combination was given with food (90% Cl of AUC 0-∞ of fasted state vs fed state, 115–127). Conclusions: The single-dose pharmacokinetic profiles of oxycodone and ibuprofen in these healthy volunteers were similar when these 2 drugs were given as monotherapy or in combination, suggesting bioequivalence. Food intake before administration of a single dose of the combination did not affect ibuprofen absorption but marginally increased the extent, but not the rate, of oxycodone absorption.

NIGHTTIME DOSING OF OMEPRAZOLE IMMEDIATE-RELEASE ORAL SUSPENSION RAPIDLY DECREASES NOCTURNAL GASTRIC ACIDITY

Purpose: Proton pump inhibitors (PPIs) suppress gastric acid secretion sufficiently to treat most symptoms of GERD. However, in some patients, PPIs fail to control nighttime gastric acid secretion and also fail to control nighttime GERD symptoms. The PPIs used to treat these symptoms have all been delayed-release formulations with enteric coatings. A new omeprazole immediate-release suspension (OME-IR[SUSP]) has been developed, using sodium bicarbonate to protect the acid-labile PPI, rather than the traditional delayed-release enteric coating. The present trial was conducted to evaluate the effectiveness of OME-IR(SUSP) in controlling nighttime gastric acidity after twice-daily (b.i.d.) dosing. Methods: Seventeen healthy subjects were enrolled in this open-label trial. Single 20-mg doses of OME-IR(SUSP) (Santarus, San Diego) were given 1 hr prior to breakfast (qAM) for 7 days. On Day 8, the 20-mg suspension was given b.i.d.: at 0830 hrs (1 hr prior to a standardized high-fat breakfast) and at 2200 hrs (bedtime). On Days 7 and 8, standardized lunch and dinner were given at 1300 and 1800 hrs. Gastric pH was continuously monitored (Medtronic) for 24 hrs following the morning doses on Days 7 and 8. The percent time pH was >4 was assessed for the 8-hr nighttime period (2200-0600 hrs) and for the 24-hr period following the morning dose. The proportion of subjects with “nocturnal acid breakthrough” (NAB) (> 1 hr of continuous pH <4) was assessed for the 8-hr nighttime period. Results: The figure below displays the 24-hr median gastric pH profile at steady state for b.i.d. dosing of OME-IR 20 mg. After the bedtime dose, OME-IR 20 mg abruptly raised the gastric pH and sustained this effect for approximately 8 hrs. The median % time pH was >4 was greater for b.i.d dosing (87%) than for qAM dosing (39%) (p <0.001). NAB occurred in fewer subjects dosed b.i.d. (5/17 [29%]) than dosed qAM (13/17 [76%]) (p = 0.005).[figure 1]FigureConclusions: Twice-daily dosing (before breakfast and at bedtime) with OME-IR(SUSP) is effective in controlling nighttime acidity. Nighttime administration of OME-IR(SUSP) may be more effective in controlling nighttime GERD symptoms than delayed-release PPIs.

The effect of food on and the intra-subject variability of the pharmacokinetics of ZD6474, a novel antiangiogenic agent, in healthy subjects

3167 Background: ZD6474 is an orally available, vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor that also has activity against epidermal growth factor receptor (EGFR) tyrosine kinase, which is currently under Phase II evaluation in a range of tumor types. The effect of food on the absorption characteristics of ZD6474 are not known, therefore these studies have a restriction on dosing with food. The effect of food on the pharmacokinetics of ZD6474 has now been assessed in healthy male volunteers. In the same study intra-subject variability in pharmacokinetics was also determined to ensure correct sizing of future clinical pharmacology studies. Methods: Sixteen volunteers were randomized to receive a single oral dose of ZD6474 (300 mg) on each of three occasions: once 30 minutes after a standard high-fat breakfast and twice under fasted conditions, or once under fasted conditions and twice 30 minutes after a standard high-fat breakfast. Due to the long half-life of approximately 10 days there was a 6-week washout between each treatment period. The effect of food on the absorption of ZD6474 compared with fasted conditions was assessed using the criteria for establishing bio-equivalence based on the end-points of Cmax and AUC. These parameters were also used to assess the intra-subject variability. Results: Statistical analysis of provisional data showed there was no clinically significant effect on either Cmax or AUC of ZD6474 when dosed with food compared with the fasted state. In addition, the overall intra-subject variability of ZD6474 was small (coefficients of variation [CVs] of 8% and 11% for AUC and Cmaxrespectively), and appears to decrease when ZD6474 is taken with food (AUC CVs of 5% and 10% and Cmax 10% and 13% for fed and fasted respectively). Conclusions: These data indicate that the restriction on dosing with food can be removed from patient studies with the assurance that the day to day variability in exposure to ZD6474 will not increase as a result of patients taking their daily ZD6474 dose with or without food. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca

The effect of food on and the intra-subject variability of the pharmacokinetics of ZD6474, a novel antiangiogenic agent, in healthy subjects

3167 Background: ZD6474 is an orally available, vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor that also has activity against epidermal growth factor receptor (EGFR) tyrosine kinase, which is currently under Phase II evaluation in a range of tumor types. The effect of food on the absorption characteristics of ZD6474 are not known, therefore these studies have a restriction on dosing with food. The effect of food on the pharmacokinetics of ZD6474 has now been assessed in healthy male volunteers. In the same study intra-subject variability in pharmacokinetics was also determined to ensure correct sizing of future clinical pharmacology studies. Methods: Sixteen volunteers were randomized to receive a single oral dose of ZD6474 (300 mg) on each of three occasions: once 30 minutes after a standard high-fat breakfast and twice under fasted conditions, or once under fasted conditions and twice 30 minutes after a standard high-fat breakfast. Due to the long half-life of approximate...

Pharmacokinetic profile of a new controlled-release isosorbide-5-mononitrate 60 mg scored tablet (Monoket Multitab ®)

The influences of food, tablet splitting, and fractional dosing on the pharmacokinetics of a new controlled-release double-scored tablet containing 60 mg isosorbide-5-mononitrate (Monoket Multitab ®) were investigated in healthy male volunteers. Food interaction was evaluated after single dose administration under fasted conditions and after a standard high-fat breakfast. The effect of tablet splitting was assessed at steady-state, after 5 days of once daily dosing with the tablet taken intact or trisected. The influence of fractional dosing was assessed after 1 and 6 days of daily regimen of 40 mg in the morning (2/3 of a tablet) and 20 mg in the evening (1/3 of a tablet). The pharmacokinetics of isosorbide-5-mononitrate after taking the tablet intact or in three fragments were very similar with a mere 10% increase of maximum plasma concentration ( C max) for the latter, while the time to peak ( T max) decreased from 5 to 4 h and areas under the concentration vs. time curves (AUCs) were virtually unchanged. Morning trough concentration reached 53 and 46 ng/ml, respectively. Administration of the intact tablet after a high-fat breakfast increased C max by 18% and AUC by 21%, and slightly delayed T max from 5 to 6 h. During fractional dosing, morning and evening C max reached 364 and 315 ng/ml on the first day, and 373 and 300 ng/ml on the 6th day, respectively. The ratio of AUC 0–24 h on the last day to AUC∞ on the first day, was 82.1% (confidence limits 71.7–94.1%) possibly resulting from peripheral volume expansion. The release characteristics of Monoket Multitab ® are thus moderately influenced by concomitant intake of food and to a very minor extent by tablet breaking. Fractional dosing allows to achieve lower peak and higher morning trough levels, while total exposure is comparable to that during once daily dosing (AUC 0–24 h, s.s. of 5.55±1.78 and 5.71±1.08 μg h/ml).

Bioavailability of amiodarone tablets administered with and without food in healthy subjects

The tablet form of amiodarone is indicated for the treatment of recurrent ventricular fibrillation or hemodynamically unstable ventricular tachycardia. It is recommended that the tablet be taken with meals in cases of gastrointestinal intolerance. However, the effect of food on its bioavailability is unknown. The primary objective of this study was to determine the effect of food on the bioavailability of amiodarone. This was a 2-period crossover study conducted in 30 healthy male subjects. Subjects were randomly assigned to 1 of 2 sequences in which the following 2 treatments were administered: (1) a single-dose of amiodarone (three 200-mg Cordarone tablets) after an overnight fast, and (2) the same dose immediately after a standard high-fat breakfast. Plasma concentrations of amiodarone and desethylamiodarone (DEA) were measured for 6 weeks after each dose. Food enhanced the extent of absorption, resulting in a peak concentration (Cmax) and area under the curve (AUCT) 3.8 and 2.4 times the respective values under fasting conditions. Food also significantly increased the rate of absorption, reducing the time (tmax) to Cmax from 7.1 to 4.5 hours. The effect of food on DEA levels was significant but less pronounced. An in vitro dissolution study confirmed a marked difference between amiodarone release under simulated fed and fasting conditions. Thus, food significantly enhances both the rate and extent of absorption of amiodarone, which is attributed partially to the effect of food on drug release from its formulation. Therefore, it is recommended that amiodarone tablets be taken consistently with meals.

Effects of food on the pharmacokinetics of sparfloxacin

Sparfloxacin, a fluoroquinolone with a broad antimicrobial spectrum and long elimination half-life, is indicated for the treatment of community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis in adult patients. The present study was undertaken to determine the effects of skim milk and a high-fat breakfast without milk on the single-dose pharmacokinetic characteristics of this antibiotic. The pharmacokinetics of a single 200-mg dose of sparfloxacin were assessed in a 3-way crossover study that included 23 healthy male volunteers who had fasted, had ingested 240 mL of skim milk, or had consumed a standard high-fat breakfast. The subjects' mean age and weight were 26.5 years and 73.2 kg, respectively; 17 were white, 5 Hispanic, and 1 black. Neither skim milk nor the high-fat breakfast had a statistically significant effect on sparfloxacin absorption, as reflected in the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC). Ninety percent confidence limits for logarithmically transformed AUC from time zero to infinity and C max were within the 80% to 125% range, demonstrating that the rate and extent of sparfloxacin absorption with skim milk or a high-fat breakfast were not different from those under fasted conditions. As indicated by an increase in the time to C max from 3.6 to 5.4 hours, the high-fat breakfast slightly delayed the onset of sparfloxacin absorption. Skim milk and the high-fat breakfast did not significantly affect the elimination kinetics of sparfloxacin. Sparfloxacin was well tolerated in all 3 treatment groups. Despite the apparent delay in the onset of absorption, the bioavailability of sparfloxacin in the healthy male subjects in this study population was not affected by concomitant administration with skim milk or a high-fat meal. Accordingly, the results suggest that sparfloxacin can be administered without regard to the ingestion of milk or meals.