ABSTRACT:Panax notoginseng (Sanqi) is a cardiovascular herb containing ginsenosides that are believed to be responsible for the therapeutic effects of Sanqi. The aim of this study was to evaluate rat exposure to ginsenosides after oral administration of Sanqi extract and to identify the key factors affecting their absorption and disposition. Ginsenosides were administered to rats, either in the form of Sanqi extract or as pure chemicals. The ginsenosides Ra 3 , Rb 1 , Rd, Re, Rg 1 , and notoginsenoside R 1 were the major saponins present in the herbal extract. Systemic exposure to ginsenosides Ra 3 , Rb 1 , and Rd after oral administration of the extract was significantly greater than that to the other compounds. Considerable colonic deglycosylation of the ginsenosides occurred, but the plasma levels of deglycosylated metabolites were low in rats. Poor membrane permeability and active biliary excretion are the two primary factors limiting systemic exposure to most ginsenosides and their deglycosylated metabolites. In contrast with other ginsenosides, biliary excretion of ginsenosides Ra 3 and Rb 1 was passive. Meanwhile, the active biliary excretion of ginsenoside Rd was significantly slower than that of other saponins. Slow biliary excretion, inefficient metabolism, and slow renal excretion resulted in long-circulating and thus relatively high exposure levels for these three ginsenosides. For these reasons, plasma ginsenosides Ra 3 , Rb 1 , and Rd were identified as pharmacokinetic markers for indicating rat systemic exposure to Sanqi extract. This is a systematic investigation of the absorption and disposition of ginsenosides from an herb, the information gained from which is important for linking Sanqi administration to its medicinal effects.

PURPOSE. To characterize ranibizumab pharmacokinetics in patients with AMD. METHODS.A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months. RESULTS.A total of 696 concentration-time records from 229 subjects with one or more measurable total serum ranibizumab concentrations were analyzed. The systemic concentration-time data for ranibizumab were best described by a one-compartment model with first-order absorption into and first-order elimination from the systemic circulation. Vitreous elimination half-life (t 1/2 ) was calculated to be 9 days and the intrinsic systemic elimination t 1/2 was calculated to be approximately 2 hours. Following ITV administration, ranibizumab egresses slowly into the systemic circulation, resulting in an apparent serum t 1/2 of 9 days. Systemic-to-vitreous exposure ratio was estimated to be 1:90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steadystate for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times.CONCLUSIONS. Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.) (Invest Ophthalmol Vis

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PURPOSE The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study. PATIENTS AND METHODS Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.

ABSTRACT:Cardiotonic pills are a type of cardiovascular herbal medicine. To identify suitable pharmacokinetic (PK) marker(s) for indicating systemic exposure to cardiotonic pills, we examined the in vivo PK properties of putatively active phenolic acids from the component herb Danshen (Radix Salviae miltiorrhizae). We also performed in vitro and in silico assessments of permeability and solubility. Several phenolic acids were investigated, including tanshinol (TSL); protocatechuic aldehyde (PCA); salvianolic acids A, B, and D; rosmarinic acid; and lithospermic acid. Plasma TSL exhibited the appropriate PK properties in dogs, including dose-dependent systemic exposure in area under concentration-time curve (AUC) and a 0.5-h elimination half-life. In rats, more than 60% of i.v. TSL was excreted intact into the urine. In humans, we found a significant correlation between the urinary recovery of TSL and its plasma AUC. The absorption rate and bioavailability of TSL were not significantly different whether cardiotonic pills were given p.o. or sublingually. The gender specificity in plasma AUC disappeared after body-weight normalization, but the renal excretion of TSL was significantly greater in women than in men. PCA was predicted to be highly permeable according to in vitro and in silico studies; however, extensive presystemic hepatic elimination and degradation in the erythrocytes led to extremely low plasma levels and poor dose proportionality. Integrated in vivo, in vitro, and in silico studies on the other phenolic acids showed poor gut permeability and nearly undetectable levels in plasma and urine. In conclusion, plasma and urinary TSL are promising PK markers for cardiotonic pills at the tested dose levels.The use of herbal therapies is escalating worldwide. However, the basis for the therapeutic effects is often poorly interpreted, and the safety, dose, and potential herb-drug interactions require better estimation (Fugh-Berman, 2000;De Smet, 2002;Lazar, 2004). Unlike most synthetic drugs, herbal medicinal products usually contain numerous chemical constituents, especially traditional Chinese medicines that often use a combination of multiple herbs.Determining which constituents of an herbal product have favorable drug-like properties will extend our knowledge of the basis for pharmacological efficacy and safety. An herbal constituent can be defined as drug-like when it possesses the desired potency, a wide safety margin, and appropriate pharmacokinetic (PK) properties and exists in adequate abundance in the herbal product. A deficit in these properties limits the usefulness of the herbal constituent for the herbal product. For a drug, the pharmacologic effect is attained when the drug or its active metabolite reaches and sustains an adequate concentration at an appropriate site of action; this hypothesis should also be applied to the herbal product. Both the dose levels and fates of active constituents in the body govern their target-site concentrations after administration of an herbal product. The releva...