Alan F. Parr

Effect of sodium acid pyrophosphate on ranitidine bioavailability and gastrointestinal transit time

During development of a ranitidine effervescent oral solution dosage form, a marked decrease was observed in the extent of ranitidine absorption relative to the conventional oral tablet. Two studies were conducted in healthy volunteers to confirm the involvement of an excipient, SAPP (sodium acid pyrophosphate), and the mechanism of interaction, altered gastrointestinal transit. The first study (n = 12) involved single-dose crossover comparisons of (A) 150 mg ranitidine with 1132 mg SAPP versus (B) 150 mg ranitidine and (C) 150 mg ranitidine with all the effervescent tablet excipients except SAPP versus (D) a 150-mg ranitidine effervescent tablet, all administered as oral solutions. Serum ranitidine AUC, Cmax, and tmax were compared using two one-sided t test 90% confidence intervals (CI). Comparing treatments A to B and D to C, all 90% CI were below the 80–120% range, indicating significantly less extensive ranitidine absorption (54% based on AUC) from the oral solutions containing SAPP. The second study (n = 12) was a single-dose crossover comparing 50 µCi 111InCl solutions with and without 1132 mg SAPP. Gastrointestinal transit times, determined by scintigraphic imaging, were compared between treatments. Gastric emptying time was unchanged, but small intestinal transit time was decreased to 56% in the presence of SAPP. More rapid small intestinal transit associated with an excipient of a solution dosage form apparently resulted in a decreased extent of ranitidine absorption. This observation contradicts the conventional wisdom that oral solutions are unlikely to fall short of bioequivalence relative to solid oral formulations.

Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'.

In 2008, this group published a paper on approaches for two-stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second-stage sample size based on the variance estimated from the first-stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright

The use of the InteliSite® Companion device to deliver mucoadhesive polymers to the dog colon

The aims of this study were two-fold; first to report on the use of the novel InteliSite Companion device to deliver material to the colon, and second to use this new technology to assess the potential of mucoadhesive polymers to be retained in the large intestine. In this three-way crossover study in beagle dogs, two mucoadhesive polymers and a non-mucoadhesive polymer were remotely delivered in powder form to the colon. The retention of 150mg doses of the radiolabelled mucoadhesive polymers Carbopol 980 and polycarbophil AA-1, and the retention of ethylcellulose (control) in the colon of three canines was examined using gamma scintigraphy. The InteliSite Companion device had a mean gastric emptying time of 1.0+/-0.8h and a mean caecal arrival time of 2.3+/-1.0h. The device was remotely activated to expel the polymers at the caecum. Although incomplete release was noted with all polymers, Carbopol 980 was found to have increased retention in the proximal colon of all three dogs. The mean retention time within the proximal colon for Carbopol 980 (15.3+/-1.4h) was significantly higher than that of polycarbophil AA-1 (10.0+/-5.7h) and the control (7.1+/-1.4h) (p<0.05). The increased colon retention time demonstrated by Carbopol 980 may be suggestive of a mucoadhesive effect.

Evaluation of the Feasibility and Use of a Prototype Remote Drug Delivery Capsule (RDDC) for Non-Invasive Regional Drug Absorption Studies in the GI Tract of Man and Beagle Dog

AbstractPurpose. Evaluate a prototype Remote Drug Delivery Capsule (RDDC) for use in beagle dogs and human volunteers for non-invasive drug absorption studies in different regions of the gastrointestinal tract. Methods. The device was dual radiolabeled and GI transit of the RDDC was monitored by gamma scintigraphy. Beagles were used initially to demonstrate the functional utility of the device where a solution of ranitidine hydrochloride (150 mg) was non-invasively delivered to the stomach, proximal small intestine and distal small intestine. A subsequent first time in human study enrolled twelve healthy male volunteers where the intended site of release was the stomach, early small bowel, distal small bowel or colon. Results. Preliminary studies conducted in beagles indicated that the RDDC operated successfully and the onset of ranitidine serum levels were dependent on the time of capsule activation and site of drug release. Results from the human study showed that all twelve subjects swallowed the device with no discomfort. Mean gastric emptying of the RDDC was 1.50 ± 1.28 h (range = 0.25 to 4.25 h), and total small intestine transit was 4.79 ± 1.82 h (range = 2.00 to 8.25 h). The capsule was retrieved from the feces at 30.25 ± 15.21 h (range = 14.12 to 74.25 h) and there were no reported adverse events. The prototype RDDC operated successfully in nine of the twelve human volunteers and the cause for the three failures was attributed to mechanical failure while the electronics assembly performed favorably. Conclusions. This prototype remote control capsule was shown to be well tolerated and functional to use in human volunteers as well as beagles. The application of the device coupled with gamma scintigraphy has the potential to be a valuable and rapid method to non-invasively evaluate regional drug absorption in the gastrointestinal tract under conditions that are both pharmaceutically and physiologically meaningful.

Use of the InteliSite® capsule to study ranitidine absorption from various sites within the human intestinal tract

AbstractPurpose. The purpose of this study was to evaluate the extent of ranitidine absorption from an externally activated drug-delivery system in two distinct regions of the intestine (jejunum and ileum) in healthy human volunteers. This investigation also was designed to evaluate the utility of the InteliSite® capsule for studying regional intestinal drug absorption in humans. Methods. The intestinal absorption of ranitidine from the jejunum and ileum was compared in eight, healthy volunteers in this open-label, two-way crossover study. In two of the eight volunteers, absorption from the colon also was studied. Subjects swallowed the capsule containing ranitidine solution (121 mg) and 100 μCi of 99mTc-DTPA. The endcap of the capsule contained 20 μCi of 111In-DTPA. At the desired intestinal site, the capsule was activated by the application of an external RF magnetic signal (6.78 MHz operating frequency) and the ranitidine solution was released. Blood samples were collected from a forearm vein for 12 hours after capsule activation. Results. The capsule released the ranitidine solution when activated in the jejunum, ileum and colon (visualized by the gamma camera). There was no difference in the extent of ranitidine absorption or ranitidine pharmacokinetics when the capsule was activated in the jejunum or ileum. Conclusions. This study demonstrates the utility of a novel, externally activated drug-delivery system to assess site-specific intestinal drug absorption in humans. Results indicate that use of the InteliSite® capsule method to evaluate site-specific intestinal ranitidine absorption in humans yields data similar to that obtained previously by means of oral intubation studies.

Dual-Isotope Imaging of Neutron-Activated Erbium-171 and Samarium-153 and the in Vivo Evaluation of a Dual-Labeled Bilayer Tablet by Gamma Scintigraphy

The feasibility of dual-label scintigraphic studies which use the neutron-activated isotopes erbium-171 and samarium-153 is described. Experimental details are provided to correct and minimize the compton scatter contribution of 171Er into the lower-energy 153Sm window. The results from this study demonstrate that this dual-label procedure is sensitive enough to monitor simultaneously the behavior of two discrete regions of the same unit dose in the gastrointestinal tract of man.

Optimal adaptive sequential designs for crossover bioequivalence studies

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70-143% within each of two ranges of intra-subject coefficient of variation (10-30% and 30-55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at ≥ 80%, their average sample sizes were similar to or less than those of conventional single stage designs.

Re-introduction of a novel approach to the use of stable isotopes in pharmacokinetic studies.

The purpose of this investigation is to evaluate the scientific benefits of a novel approach in using stable isotopes to reduce the number of subjects needed to perform relative bioavailability and bioequivalence pharmacokinetic studies for formulations that are qualitatively and quantitatively the same and quality by design (QbD) pharmacokinetic studies. The stable isotope approach was investigated using simulations to determine the impact this approach would have on the estimation of variability and, subsequently, the sample size for a bioequivalence study. A biostudy was conducted in dogs in a two period crossover to explore the viability of the stable isotope approach. For a drug product with within-subject variability (CVw) of 50% and assuming a correlation of 0.95 between the enriched and non-enriched pharmacokinetics (PK), simulations showed that the variability can be reduced by 70% and the required sample size can be reduced by 90% while maintaining 90% power to demonstrate bioequivalence. The dog study showed a strong correlation (R2, > 0.99) between the enriched and non-enriched area under the curve and maximum observed concentration, and a significant reduction in the variability (reduction in % coefficient of variation from 79.9% to 6.3%). Utilization of a stable isotope approach can markedly improve the efficiency and accuracy of bioavailability and bioequivalence studies particularly for highly variable drugs in formulations that are qualitatively and quantitatively the same and for studies designed for QbD investigations.

Solubility Criteria for Veterinary Drugs

This Stimuli article is the first step toward the development of a general chapter addressing solubility criteria for veterinary drug products. The current criteria for classifying drug solubility are based on human gastrointestinal (GI) physiology. These criteria may not be appropriate to the unique conditions encountered within the GI tract of veterinary species. Thus, this article discusses the relationship between the species-specific GI characteristics and the criteria appropriate for describing drug solubility in veterinary species. Initially the discussion focuses on dogs and cattle, the most common veterinary patients in small- and food-animal practices, respectively. Later the discussion will include various other veterinary species of interest.

Determination of Thermodynamic Solubility of Active Pharmaceutical Ingredients for Veterinary Species: A New USP General Chapter

This Stimuli article discusses the approach for the development of a new general chapter on solubility determination for veterinary drug products. Possible procedures are discussed, with emphasis on the shake-flask method. Recommendations are included on the test conditions for products to treat dogs and cattle. The Expert Panel welcomes comments from the public and stakeholders. dx.doi.org/10.14227/DT240117P36