Low level determinations of methyl methanesulfonate and ethyl methanesulfonate impurities in Lopinavir and Ritonavir Active pharmaceutical ingredients by LC/MS/MS using electrospray ionization

Methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) have been highlighted as potential genotoxic impurities (PGIs). A sensitive LC/MS/MS method is developed and validated for the determination of MMS and EMS impurities in both Lopinavir and Ritonavir Active pharmaceutical ingredient. Method utilizes, Atlantis T3 column with electrospray ionization in multiple reactions monitoring (MRM) mode for quantitation of impurities. The proposed method is specific, linear, accurate and precise. The calibration curves show good linearity over the concentration range of 0.01-0.23 μg/mL for MMS and 0.005-0.23 μg/mL for EMS. The correlation coefficient obtained is >0.99 in each case. Method has very low limit of detection (LOD) and quantification (LOQ). LOD and LOQ of MMS and EMS are as low as ～0.002 μg/mL and ～0.01 μg/mL respectively. Method has accuracy within 80-120% for both the analytes. This method is a good quality control tool for quantitation of MMS and EMS impurities at very low levels in Lopinavir and Ritonavir.     

Dose optimization with population pharmacokinetics of ritonavir-boosted lopinavir for Thai people living with HIV with and without active tuberculosis

BackgroundPrior to dolutegravir availability, ritonavir-boosted lopinavir (LPV/r) was an alternative recommendation when first-line drugs could not be used. A high concentration of protease inhibitors was observed in the Thai people living with HIV (PLWH). Thus, dose reduction of LPV/r may be possible. However, the pharmacokinetics and dose optimization of LPV/r have never been investigated. This study aimed to develop a population pharmacokinetic model of LPV/r and provide dosage optimization in Thai PLWH.MethodsLPV and RTV trough concentrations from Thai PLWH were combined with intensive data. The data were analyzed by the nonlinear mixed-effects modeling approach. The influence of RTV concentration on LPV oral clearance (CL/F) was investigated.ResultsRifampicin (RIF) use increased LPV and RTV CL/F by 2.16-fold and 1.99-fold, respectively. The reduced dose of 300/75 and 200/150 mg twice daily provided a comparable percentage of patients achieving LPV target trough concentration to the standard dose for PI-naïve patients. For HIV/TB co-infected patients receiving RIF who could not tolerate the recommended dose, the reduced dose of 600/150 mg twice daily was recommended.ConclusionThe population pharmacokinetic model was developed by integrating the interaction between LPV and RTV. The reduced LPV/r dosage offers sufficient LPV exposure for Thai PLWH.     

Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution Rate

This study reports the development of ritonavir-copovidone amorphous solid dispersions (ASDs) and dosage forms thereof using selective laser sintering (SLS) 3-dimensional (3-D) printing in a single step, circumventing the post-processing steps required in common techniques employed to make ASDs. For this study, different drug loads of ritonavir with copovidone were processed at varying processing conditions to understand the impact, range, and correlation of these parameters for successful ASD formation. Further, ASDs characterized using conventional and advanced solid-state techniques including wide-angle X-ray scattering (WAXS), solid-state nuclear magnetic resonance (ssNMR), revealed the full conversion of the crystalline drug to its amorphous form as a function of laser-assisted selective fusion in a layer-by-layer manner. It was observed that an optimum combination of the powder flow properties, surface temperature, chamber temperature, laser speed, and hatch spacing was crucial for successful ASD formation, any deviations resulted in print failures or only partial amorphous conversion. Moreover, a 21-fold increase in solubility was demonstrated by the SLS 3-D printed tablets. The results confirmed that SLS 3-D printing can be used as a single-step platform for creating ASD-based pharmaceutical dosage forms with a solubility advantage.     

3D方案治疗基因1b型低病毒载量慢性丙型肝炎患者应答疗效研究

目的 观察3D方案(帕里瑞韦/利托那韦/奥比他韦)联合达塞布韦治疗基因1b型低血清病毒载量的慢性丙型肝炎(CHC)患者的疗效及其血浆γ-干扰素(IFN-γ)和干扰素诱导蛋白10(IP-10)水平的变化.方法 2019年5月～2020年5月在我院接受治疗的基因1b型低血清病毒载量的CHC患者77例(初始治疗者62例,复治...     

A dose-escalation study of bi-daily once weekly oral docetaxel either as ModraDoc001 or ModraDoc006 combined with ritonavir

IntroductionTwo solid dispersions of docetaxel (denoted ModraDoc001 capsule and ModraDoc006 tablet (both 10 mg)) were co-administered with 100 mg ritonavir (/r) and investigated in a bi-daily once weekly (BIDW) schedule. Safety, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary activity were explored.MethodsAdult patients with metastatic solid tumours were included in two dose-escalation arms. PK sampling was performed during the first week and the second or third week. Safety was evaluated using US National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. Antitumour activity was assessed every 6 weeks according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.0.ResultsModraDoc001 capsule/r and ModraDoc006 tablet/r were administered to 17 and 28 patients, respectively. The most common adverse events were nausea, vomiting, diarrhoea and fatigue, mostly of grade 1–2 severity. Grade 3/4 neutropenia/neutropenic fever was observed in 2 patients (4%). The MTD was determined as 20/20 mg ModraDoc001/r and 30/20 mg ModraDoc006/r (morning/afternoon dose) once weekly. The mean area under the plasma concentration–time curve (AUC_0–48) ± standard deviation at the MTD for ModraDoc001/r and ModraDoc006/r were 686 ± 388 ng/ml*h and 1126 ± 382 ng/ml*h, respectively. Five partial responses were reported as best response to treatment.ConclusionOral administration of BIDW ModraDoc001/r or ModraDoc006/r is feasible. The once weekly 30/20 mg ModraDoc006 tablet/r dose-level was selected for future clinical development. Antitumour activity is promising.     

不同HIV蛋白酶抑制剂对鼠胰岛素瘤细胞功能的影响

目的：探讨不同HIV蛋白酶抑制剂对胰岛beta-细胞功能的影响。方珐：体外观察不同浓度ritonavir或amprenavir干预48h对鼠胰岛素瘤INS-1细胞葡萄糖刺激的胰岛素释放速率的影响，胰岛素测定采用ELISA法，并用细胞内DNA含量标准化。用苔盘蓝染色细胞计数、MTT试验评估ritonavir或amprenavir对INS-1细胞活力的影响。结果：Ritonavir治疗可以显著降低基础胰岛素分泌速率及葡萄糖刺激的胰岛素释放速率，并呈剂量依赖关系（r分别为-0．861，-0．839，均P〈0．01）。10μmol／L ritonavir分别降低基础胰岛素分泌和葡萄糖刺激的胰岛素释放达46％和47％。Amprenavir对胰岛素释放功能没有影响。结论：不同HIV蛋白酶抑制剂对胰岛beta-细胞功能的影响不同。     

Micellar electrokinetic chromatography method development for determination of impurities in Ritonavir

Ritonavir is a synthetic peptidomimetic human immunodeficiency virus (HIV) protease inhibitor employed in the treatment of AIDS since 1996. Synthetic precursors are potential impurities in the final product. In the present work a micellar electrokinetic chromatography (MEKC) method for the separation of Ritonavir from three available synthetic precursors was developed. The optimized separation is performed in a background electrolyte composed of sodium tetraborate (pH 9.6; 15 mM) containing sodium dodecylsulfate (30 mM) and acetonitrile (18%, v/v). Mass spectrometry was used to confirm the identity of the tested substances. Good repeatability was observed for migration time (RSD about 0.4%) and peak area (RSD about 0.8%). The limits of detection (LOD) obtained allow the determination of two of the impurities at levels as low as 0.005% m/m, and one at a level of 0.3% m/m.