Designing biorelevant dissolution tests for lipid formulations: Case example – Lipid suspension of RZ-50

Biorelevant dissolution test methods for lipid formulations of RZ-50, an experimental Roche compound, were developed and compared with standard compendial methods in terms of their in vivo predictability. Release of RZ-50, a poorly soluble weakly acidic drug, from lipid suspensions filled in soft gelatin capsules was studied in compendial and biorelevant media using the USP Apparatus 2 (paddle method) and the USP Apparatus 3 (Bio-Dis method). Pharmacokinetic data were obtained in dogs after oral administration of a single 2.5mg dose of RZ-50 soft gelatin capsules in the postprandial state. Level A IVIVC analysis and curve comparison of fraction drug dissolved vs. absorbed using the Weibull distribution were used to evaluate the in vitro methods in terms of their ability to fit the in vivo plasma profiles. Very low drug release was observed with the paddle method owing to poor dispersibility of the lipids in the dissolution media, whereas the Bio-Dis method hydrodynamics facilitated release of the drug by emulsifying the formulation in the medium. The best IVIVC was obtained using a dissolution medium representing fed gastric conditions in combination with the Bio-Dis method. Curve comparisons of the fraction drug absorbed and the fraction drug dissolved profiles based on Weibull distribution fits yielded similar results. The Bio-Dis/biorelevant in vitro method appears to be suitable for this type of lipid formulation.     

Towards Quantitative Prediction of Oral Drug Absorption

Although several routes of administration can be considered for new drug entities, the oral route remains the most popular. To predict the in vivo performance of a drug after oral administration from in vitro data, it is essential that the factors limiting absorption can be modelled. Factors limiting oral drug absorption are typically slow and/or incomplete dissolution, formation of insoluble complexes and/or decomposition in the gastrointestinal lumen, poor net permeability and first-pass metabolism. Although many attempts have been made to make global forecasts of oral bioavailability based on a single parameter (ranging from the partition coefficient [logP] to the polar surface area), it is clear from the diversity of properties that can influence delivery of drugs via the oral route that such an approach can at best lead to a qualitative estimation. To predict in vivo performance in a more quantitative way, it is instead necessary to identify the extent to which each of the aforementioned factors can limit absorption, and then combine the information into a comprehensive model of the absorptive processes. Much progress has been made in the last 10 years on developing methods to pin down the extent to which each of the factors actually limits the absorption of a given compound and, concomitantly, physiological models have been evolved, which show promise in terms of being able to integrate the information generated about each of the individual limiting factors. This article attempts to summarize recent progress on the various fronts as a kind of 'progress report' towards quantitative prediction of oral drug absorption.     

Outcome of patients with newly diagnosed primary CNS lymphoma after high-dose methotrexate followed by consolidation whole-brain radiotherapy and cytarabine: an 8-year cohort study

International Journal of Clinical Oncology - Addition of cytarabine to high-dose methotrexate (HD-MTX) chemotherapy improves outcome of primary CNS lymphoma (PCNSL); however, the combination...     

Types,Clinical Features,and Survival Outcomes of Patients with Acute Myeloid Leukemia in Thailand: A 3-Year Prospective Multicenter Study from the Thai Acute Leukemia Study Group (TALSG)

BackgroundAcute myeloid leukemia (AML) is a common, challenging hematologic malignancy worldwide. Thai data on its characteristics and outcomes have never been systematically reported, to our knowledge. The objective of this study was to determine the clinical features and outcomes of Thai patients with AML.Patients and MethodsThis was a prospective observational study of nine academic hospitals. Patients with newly diagnosed AML were invited to register online.ResultsA total of 679 patients with AML were included. The presence of circulating peripheral blood blasts was correlated with a high white blood cell count. Acute promyelocytic leukemia (APL) had predominantly lower white blood cell counts and higher proportions without peripheral blood blasts compared with non-APL AML. Disseminated intravascular coagulation was commonly presented in APL (37.7%). Splenomegaly and normal platelet count were more frequently seen in patients with Philadelphia chromosome–positive AML. The median follow-up time for those who survived more than 1 year was 28.0 months. One-year overall survival rates for non-APL AML and APL were 31.9% and 88.2%, respectively; 2-year overall survival rates were 29.6% and 88.2%, respectively. Hematopoietic stem cell transplantation could improve survival in non-APL AML.ConclusionAPL should be considered despite absence of peripheral blood blast. This study demonstrates poor outcome of Thai AML and more research to improve outcomes are underway. Expanding access to hematopoietic stem cell transplantation should be considered in Thailand.     

Infections in patients with aplastic Anemia in Chiang Mai University

Background

Infection is a major complication in aplastic anemia (AA) patients. Primary objectives of this study were to determine the prevalence of infections and to determine types of pathogens associated with infections in patients with AA. Secondary objectives were to evaluate overall survival after infections as well as risk factors of infections in patients with AA.

Methods

The authors retrospectively evaluated the infectious episodes (IEs), type of infections, associated pathogens, and outcomes of infections in patients with AA who were diagnosed and treated at Chiang Mai University between January 2010 and December 2015.

Results

Sixty-seven patients with a median age of 51 years (range, 15–87 years) were enrolled. Forty two patients (62.6%) were severe AA. Median absolute neutrophil count (ANC) was 984 /mm³ (range, 120–5500/mm³). Twenty five patients (37.3%) received antithymocyte globulin plus cyclosporine A, 41 patients (61.1%) received anabolic hormone, and 2 patients (2.9%) underwent allogeneic hematopoietic stem cell transplantation. Overall, 31 IEs were documented in 22 patients (32.8%). The most common microbiologically documented site of infection was bloodstream infection (23.4%) followed by pulmonary infection (14.9%). Culture-negative febrile neutropenia occurred in 12.7%. Common pathogens identified were bacteria (73.9%), mainly gram-negative (52.9%) including Acinetobacter baumannii (23.5%) and Pseudomonas aeruginosa (17.6%). Fungal infections were diagnosed in 21.7% and all were Aspergillus spp. Six patients (9%) died during the study period. All of them died from infection which gram-negative bacteria were most common pathogens (66.7%). Patients with infections had 5-year overall survival of 72% that is significantly less than patients without infection (100%) (p?=?0.0002). Only risk factor that correlates with high probability of infection was ANC?<?500/mm³. (HR 2.29, 95%CI 1.03–7.72, p?=?0.043).

Conclusions

Prevalence of infections in AA patients in Chiang Mai University was 32.8% Bacterial infections especially gram-negative bacteria were the major pathogens. Patients with ANC?<?500/mm³ had higher risk of infections. Infection was the most important cause of death in AA.

     

Overexpression of Claudin-1 is Associated with Advanced Clinical Stage and Invasive Pathologic Characteristics of Oral Squamous Cell Carcinoma

Claudins constitute a group of principal proteins forming the tight junctional complex. The altered expression of selected claudins has been reported in several human cancers. The purpose of this study was to investigate the expression of claudin-1 and claudin-4 in oral squamous cell carcinoma (OSCC) and examine its relationship with patient clinical-pathologic features. Forty-five OSCC cases were enrolled. Patient clinical, pathologic and follow-up data were reviewed and the claudin-1 and claudin-4 expression was analyzed immunohistochemically. Positive claudin-1 and claudin-4 immunoreactivities were noted in 86.7 and 80 % of cases, respectively. The majority of cases showed the staining in less than 25 % of cancer cells. The increased claudin-1 expression was significantly associated with the high pathologic grade, the presence of microscopic perineural invasion, vascular invasion, nodal metastasis, and advanced clinical stage. No relationship between various clinico-pathologic parameters and differential claudin-4 expression was observed. Claudin-1 may play a role in OSCC progression and could serve as a prognostic marker of advanced disease.     

Sexuality and Management of Benign Prostatic Hyperplasia with Alfuzosin: SAMBA Thailand

IntroductionBenign prostatic hyperplasia (BPH) is a common condition among elderly men. The aim of therapy is to improve lower urinary tract symptoms (LUTS) and quality of life (QoL) and to prevent complications.AimThe primary objective was to assess the effect on ejaculatory dysfunction (EjD) of 6 months treatment with alfuzosin (XATRAL) 10 mg once daily (OD) in men with LUTS suggestive of BPH in Thailand. Secondary objectives were to evaluate the efficacy of alfuzosin on LUTS, bother score (International Prostate Symptom Score [IPSS] 8th question), erectile dysfunction (ED), onset of action, and tolerability.MethodsOverall, 99 men with moderate to severe LUTS suggestive of BPH (mean IPSS 18.9, bother score 4.3) were enrolled in an open-label study. Sexual function was evaluated at baseline and after 6 months treatment, using the International Index of Erectile Function-5 and the Male Sexual Health Questionnaire (MSHQ) ejaculation score, a new validated questionnaire assessing seven EjD symptoms.Main Outcome MeasureThe main outcome measure is mean change from baseline to the end of treatment in the MSHQ Ejaculation score.ResultsMHSQ ejaculation score significantly improved from 23.09 at baseline to 21.54 at 6 months (P = 0.022). Overall, 70% of patients perceived an improvement in LUTS within 1 week (36.3% within 3 days). IPSS total score significantly improved from 18.93 at baseline to 9.59 at 6 months (P < 0.001). IPSS voiding and irritative subscores also significantly improved. The percentage of patients with moderate or severe ED decreased from 35.3% at baseline to 21.8% at 6 months. Most adverse events were dizziness (3%) and orthostatic hypotension (1%) with minor intensity. No significant change in blood pressure and heart rate was observed.ConclusionsAlfuzosin 10 mg OD administered for 6 months provides a marked and rapid (within 1 week) improvement in LUTS and bother score while improving both ED and EjD. Leungwattanakij S, Watanachote D, Noppakulsatit P, Petchpaibuol T, Choeypunt N, Tongbai T, Wanamkang T, Lojanapiwat B, Permpongkosol S, Tantiwong A, Pripatnanont C, Akarasakul D, Kongwiwatanakul S, and Chotikawanich E. Sexuality and management of benign prostatic hyperplasia with alfuzosin: SAMBA Thailand.     

Improved Survival of Elderly-fit Patients With Acute Myeloid Leukemia Requiring Intensive Therapy: 3-Year Multicenter Analysis From TALWG

Background

Elderly patients with acute myeloid leukemia (AML) have a poorer prognosis than younger ones. Several factors contribute to the poor outcomes for this patient group.

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

Objectives The dissolution characteristics of immediate‐release doxycycline hyclate products with certified in‐vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver‐based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin‐ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy‐Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in‐vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over‐discriminating. Conclusions Bioequivalence of immediate‐release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.