Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Carbamazepine.

Literature relevant to assessing whether BCS-based biowaivers can be applied to immediate release (IR) solid oral dosage forms containing carbamazepine as the single active pharmaceutical ingredient are reviewed. Carbamazepine, which is used for the prophylactic therapy of epilepsy, is a non-ionizable drug that cannot be considered "highly soluble" across the range of pH values usually encountered in the upper gastrointestinal tract. Furthermore, evidence in the open literature suggests that carbamazepine is a BCS Class 2 drug. Nevertheless, the oral absolute bioavailability of carbamazepine lies between 70 and 78% and both in vivo and in vitro data support the classification of carbamazepine as a highly permeable drug. Since the therapeutic and toxic plasma level ranges overlap, carbamazepine is considered to have a narrow therapeutic index. For these reasons, a BCS based biowaiver for IR tablets of carbamazepine cannot be recommended. Interestingly, in nine out of ten studies, USP dissolution conditions (900 mL water with 1% SLS, paddle, 75 rpm) appropriately discriminated among bioinequivalent products and this may be a way forward to predicting whether a given formulation will be bioequivalent to the comparator product.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Ondansetron.

Literature data pertaining to the physicochemical, pharmaceutical, and pharmacokinetic properties of ondansetron hydrochloride dihydrate are reviewed to arrive at a decision on whether a marketing authorization of an immediate release (IR) solid oral dosage form can be approved based on a Biopharmaceutics Classification System (BCS)-based biowaiver. Ondansetron, a 5HT3 receptor antagonist, is used at doses ranging from 4 mg to 24 mg in the management of nausea and vomiting associated with chemotherapy, radiotherapy, and postoperative treatment. It is a weak base and thus exhibits pH-dependent solubility. However, it is able to meet the criteria of "high solubility" as well as "high permeability" and can therefore be classified as a BCS class I drug. Furthermore, ondansetron hydrochloride 8 mg IR tablets (Zofran® 8 mg) and multiples thereof (16 mg = Zofran® 8 mg × 2 tablets and 24 mg = Zofran® 8 mg × 3 tablets) meet the criteria of "rapidly dissolving" in dissolution testing. Ondansetron hydrochloride has a wide therapeutic window and is well-tolerated after oral administration. Based on its favorable physicochemical properties, pharmacokinetic data and the minimal risks associated with an incorrect bioequivalence decision, the BCS-based biowaiver procedure can be recommended for ondansetron hydrochloride dihydrate IR tablets.

Laparoscopic Intracorporeal Pancreaticogastrostomy in Total Laparoscopic Pancreaticoduodenectomy-A Novel Anastomotic Technique.

Novel pancreaticogastric anastomosis technique in laparoscopic pancreaticoduodenectomy which is simple, feasible to perform, provides secure fixation between stomach and pancreas. The aim of our article is to describe our technique of intracorporeal pancreaticogastrostomy as a promising approach for future widespread application.

Novel Anastomotic Technique for Uterine Transplant Using Utero-ovarian Veins for Venous Drainage and Internal Iliac Arteries for Perfusion in Two Laparoscopically Harvested Uteri.

STUDY OBJECTIVE: To evaluate 2 cases of uterine transplant surgery that used utero-ovarian veins as outflow channels, internal iliac arteries for perfusion, and the organ harvest surgery performed laparoscopically. DESIGN: Case study (Canadian Task Force Classification III). SETTING: An urban, private, tertiary care hospital. PATIENTS: Two patients, ages 30 and 24years, diagnosed with absolute uterine factor infertility secondary to Mayer-Rokitansky-Küster-Hauser syndrome underwent related living donor uterine transplants; donors were their mothers with normal menses. INTERVENTIONS: Retrieval of organs through minilaparotomy and laparoscopic harvest of donor internal iliac arteries and ovarian veins. MEASUREMENTS AND MAIN RESULTS: Anastomosis was completed with bilateral donor internal iliac arteries to recipient internal iliac arteries in an end-to-end manner and with bilateral donor ovarian veins to recipient external iliac veins in an end-to-side manner. The lengths of utero-ovarian veins of both donors were 11 and 11cm on both sides; the lengths of the internal iliac arteries of both donors were 10 and 7.5cm on the left side and 10 and 6cm on the right side. The operative times for harvest surgery, bench surgery and transplant surgery were 2:40 and 3:20 hours, 34:32 and 33:30 min and 4:00 and 4:30 hours respectively for recipients 1 and 2. Daily postoperative uterine Doppler was completed through day 8 and then every other day and showed good intrauterine blood flow (i.e., low resistance arcuate vessel flow; resistance index < .5). Cervical biopsies on postoperative days 7 and 14 showed no evidence of rejection in either recipient. Both recipients started menstruating within 2 months of surgery. CONCLUSION: By using ovarian veins as outflow channels, the challenges involved in dissection along the internal iliac vein are avoided, and harvesting the donor internal iliac artery reduces the tension on vascular anastomosis. The selection of vessels to be harvested could make the technique reproducible, although larger studies are warranted to confirm results.

Evaluation of 5-year results of laparoscopic transhiatal oesophagectomy as a single-centre experience.

INTRODUCTION: Minimal Invasive Surgery of oesophageal cancers is gaining popularity. We have published our Thoracoscopic Esophagectomy results. The present study focuses on our expertise of TransHiatal Esophagectomy. MATERIALS AND METHODS: 287 patients underwent Esophagectomies for Cancer of Esophagus at Galaxy Care Laparoscopy Institute from January 2010 to December 2014 after thorough assesment. Out of these, 81 patients underwent laparoscopic trans hiatal esophagectomies. Their charts were reviewed retrospectively for intraoperative and postoperative results. The median follow up was 28 months. RESULTS: Out of 81 patients,76 patients had R0 resection and 5 had R1. The average lymphnode yield was 20,average survival was 28months. 3 patients had local recurrence,18 had regional recurrence and 30 had distant recurrence. Average operating time was 140 min,mean blood loss was 80 ml. Average Post-operative ICU stay was 1 day and hospital stay 7 days. CONCLUSION: Classic THE has limitations which can be overcome by the use of laparoscopic techniques. Laparoscopic approach for THE has better magnified vision facilitating better clearance under vision. Hence we recommend laparoscopic technique for THE to minimize morbidity and improve oncologic results.

Laparoscopic-Assisted Uterus Retrieval From Live Organ Donors for Uterine Transplant: Our Experience of Two Patients.

STUDY OBJECTIVE: To report the first ever laparoscopic-assisted live donor uterus retrieval in 2 patients for uterus transplant. DESIGN: Case study (Canadian Task Force classification III). SETTING: Galaxy CARE Laparoscopy Institute, Pune, India. PATIENTS: Two patients with absolute uterine factor infertility with their mothers as donors. INTERVENTIONS: In vitro fertilization and uterine transplant. MEASUREMENTS AND MAIN RESULTS: A 12-member team was formed, and approval for transplant was obtained from the institutional review board. Pretransplant, in vitro fertilization for both patients was done. Two consecutive uterine transplants were done on 2 successive days. Vessels were harvested laparoscopically in both donors. Uterus and harvested vessels were retrieved by a small abdominal incision to prevent injury and infection. The uterus was transplanted in the recipients by end to side anastomosis of the harvested vessels to external iliac vessels, followed by anchoring of supports of the donor uterus to those of the recipients. Surgical intra- and postoperative parameters, postoperative investigations, and follow-up data of 6 months were measured. Operative time for laparoscopic donor surgery was 4 hours. Bench surgery took 45 minutes. Recipient surgery time was 4 hours. There were no intraoperative or immediate postoperative complications. Both the recipients started menstruating after 34 days and 48 days, respectively, and have had 6 cycles of menses at regular intervals. Uterine artery Doppler showed good flow in both patients. Hysteroscopy-guided cervical biopsies were used as a method of surveillance of graft rejection after uterine transplant. Office hysteroscopy was done after 2 months in both patients, and hysteroscopy-guided endometrial and cervical biopsies were taken. Minimal slough was seen on the endometrium in the patient with Mayer-Rokitansky-Küster-Hauser syndrome, which was removed. Repeat hysteroscopy after 10 days showed a healthy endometrium. CONCLUSIONS: Laparoscopic-assisted uterus donor retrieval is feasible and affords all the advantages of a minimally invasive technique, thereby reducing the morbidity of the procedure. It helps in better dissection of the vessels, shortens the operative time, and helps to minimize tissue handling of the harvested uterus and vessels.

Laparoscopic-Assisted Uterus Retrieval From Live Organ Donors for Uterine Transplant.

STUDY OBJECTIVE: The authors present the first ever laparoscopic-assisted uterus retrieval in a live donor for uterus transplant. DESIGN: A step-by-step surgical demonstration. SETTING: Galaxy CARE Laparoscopy Institute, Pune, India. PATIENTS: Two patients, ages 21 and 26 years, with Mayer-Rokitansky-Küster-Hauser syndrome and Asherman syndrome, respectively, with their mothers as donors. INTERVENTIONS: A 12-member team was formed. After a review of the available literature on uterine transplant, a protocol was formulated and submitted to the Institutional Review Board (IRB). Approval from the Institutional Review Board was obtained. Thorough screening of the candidates was done. Two consecutive uterine transplants were done on 2 successive days. Vessels were harvested laparoscopically in both donors. Uterus was retrieved through a small abdominal incision, to prevent any injury to the uterus and harvested vessels. Uterus was transplanted in the recipients by end-to-side anastomosis of the harvested vessels to the external iliac vessels, followed by anchoring of supports of the donor uterus to those of the recipients. MEASUREMENTS AND MAIN RESULTS: Surgical intra- and postoperative parameters, postoperative investigations, and follow-up data of 4 months. The operative time for laparoscopic donor surgery was 4 hours. Bench surgery took 45 minutes. The recipient surgery was completed in 4 hours. There were no intraoperative or immediate postoperative complications. Both recipients started menstruating after 34 days and 48 days, respectively, and have had 3 cycles of menses at regular intervals to date. After discharge, follow-up cervical biopsies at 3 weekly intervals showed no signs of rejection. Uterine artery Doppler ultrasound showed good flow in both patients. CONCLUSION: Laparoscopic-assisted donor retrieval is feasible and affords all advantages of a minimally invasive technique. It helps in better dissection of vessels, shortens the operative time, and helps minimize tissue handling, thereby reducing the morbidity of the procedure.

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid.

This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 µg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid.

Importation of prescription medicines into New Zealand: a snapshot of intercepted products.

OBJECTIVE: The aim of this research was to describe the types of prescription medicines being imported into New Zealand. SETTING: Imported medicines intercepted at the international mail centre in Auckland and referred to the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) between July and December 2007 were studied. METHOD: During the study 3,918 prescription medicine imports were intercepted and entered into a database by Medsafe. These were categorised according to the country the medicines were posted from and medicine related details such as brand, active ingredient(s), route of administration, strength and quantity imported. Researchers systematically categorised medicines by therapeutic indications, dosage form, whether these medicines were available in New Zealand and if they were subsidised by the New Zealand government. MAIN OUTCOME MEASURE: Types of medicines imported into New Zealand and whether or not they were legally available and subsidised by the government. RESULTS: Medicines were most commonly imported from India and China. Seventy eight percent of the total medicines imported were already available in New Zealand, and of these almost half were subsidised by the government. Antibiotics contributed to a significant proportion of the total subsidised medicines imported, the most common being amoxicillin. Four of the five most commonly imported medicines could be considered 'lifestyle' medicines (sildenafil, tadalafil, finasteride and sibutramine). 'High risk' medicines were identified--for example medicines used in the treatment of tuberculosis, malignant diseases and mental health disorders. CONCLUSION: This study is the first of its kind in New Zealand to explore the types of prescription medicines imported into the country. The majority of imported medicines were classified as 'lifestyle' medicines. The study findings also identified possible negative public health implications associated with some of the imported prescription medicines, for example resistance associated with the importation of antibiotics.

Challenges and opportunities in establishing scientific and regulatory standards for assuring therapeutic equivalence of modified-release products: workshop summary report.

Modified-release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry and regulatory agencies to discuss current regulatory expectations and industry practices for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients.

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty-four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages < or = 4 years or > 4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients < or = 12 kg should be dosed at 1.1 mg/kg and those > 12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.

Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications.

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.