ABSTRACT:Silymarin, a mixture of polyphenolic flavonoids extracted from milk thistle (Silybum marianum), is composed mainly of silychristin, silydianin, silybin A, silybin B (SB B ), isosilybin A (ISB A ), and isosilybin B. In this study, the plasma concentrations of free (unconjugated), conjugated (sulfated and glucuronidated), and total (free and conjugated) silymarin flavonolignans were measured using liquid chromatography-electrospray ionization-mass spectrometry, after a single oral dose of 600 mg of standardized milk thistle extracts to three healthy volunteers. Pharmacokinetic analysis indicated that silymarin flavonolignans were rapidly eliminated with short half-lives (1-3 and 3-8 h for free and conjugated, respectively). The AUC 03ؕ values of the conjugated silymarin flavonolignans were 4-to 30-fold higher than those of their free fractions, with SB B (mean AUC 03ؕ ؍ 51 and 597 g ⅐ h/l for free and conjugated, respectively) and ISB A (mean AUC 03ؕ ؍ 30 and 734 g ⅐ h/l for free and conjugated, respectively) exhibiting higher AUC 03ؕ values in comparison with other flavonolignans. Near the plasma peak times (1-3 h), the free, sulfated, and glucuronidated flavonolignans represented approximately 17, 28, and 55% of the total silymarin, respectively. In addition, the individual silymarin flavonolignans exhibited quite different plasma profiles for both the free and conjugated fractions. These data suggest that, after oral administration, silymarin flavonolignans are quickly metabolized to their conjugates, primarily forming glucuronides, and the conjugates are primary components present in human plasma.
JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme expected to lack immunologic cross-reactivity to Escherichia coli-derived asparaginases. It is being developed as part of a multiagent chemotherapeutic regimen to treat acute lymphoblastic leukemia or lymphoblastic lymphoma patients who develop E coli-derived asparaginase hypersensitivity. A population pharmacokinetic (PopPK) model was developed for JZP-458 using serum asparaginase activity (SAA) data from a phase 1, single-dose study (JZP458-101) in healthy adults. Effects of intrinsic covariates (body weight, body surface area, age, sex, and race) on JZP-458 PK were evaluated. The model included SAA data from 24 healthy adult participants from the phase 1 study who received JZP-458: intramuscular (IM) data at 12.5 mg/m 2 (N = 6) and 25 mg/m 2 (N = 6), and intravenous (IV) data at 25 mg/m 2 (N = 6) and 37.5 mg/m 2 (N = 6). Model simulations of adult and pediatric SAA profiles were performed to explore the likelihood of achieving a therapeutic target nadir SAA (NSAA) level ≥0.1 IU/mL based on different administration strategies. PopPK modeling and simulation suggest JZP-458 is expected to achieve 72-hour NSAA levels ≥0.1 IU/mL in 100% of adult or pediatric populations receiving IM administration at 25 mg/m 2 , and in 80.9% of adult and 94.5% of pediatric populations receiving IV administration at 37.5 mg/m 2 on a Monday/Wednesday/Friday (M/W/F) dosing schedule. Based on these results, the recommended starting dose for the phase 2/3 pivotal study is 25 mg/m 2 IM or 37.5 mg/m 2 IV on a M/W/F dosing schedule in pediatric and adult patients.
Due to its narrow therapeutic index and substantial inter-patient variability in clinical response, warfarin represents an ideal drug candidate to benefit from the promise of pharmacogenomic-guided dosing strategies. Consistent with in vitro data, clinical studies have demonstrated that CYP2C9 polymorphisms significantly influence warfarin pharmacokinetics by reducing (S)-warfarin metabolic clearance, consequently lowering maintenance dose requirements and increasing the risk over-anticoagulation during the initiation phase of therapy. Recent data suggest that polymorphisms in genes encoding several pharmacodynamic determinants of the coagulation cascade may also influence warfarin's antithrombotic dose-response. Of these, VKORC1 polymorphisms account for a significant proportion of the inter-individual variability in warfarin dose requirements in all populations evaluated. Collectively, these data suggest that assessment of genetic polymorphisms affecting both warfarin pharmacokinetics and pharmacodynamics could help to predict warfarin dose requirements in patients. Therefore, the promise of pharmacogenomic-guided dosing as a useful strategy to improve clinical outcomes with warfarin therapy appears credible and warrants further investigation.
Introduction: Asparaginase Erwinia chrysanthemi (Erwinia), an asparagine-specific enzyme indicated as a component of a multiagent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E coli-derived asparaginase, is approved in the US for intramuscular and intravenous (IV) administration (Erwinaze USPI 2016). IV administration of proteins, such as asparaginase, may be associated with infusion reactions that may be mitigated by prolongation of the infusion time. Pharmacokinetic (PK) simulations based on a population PK (PPK) model were performed to evaluate PK of IV Erwinia infusions over 2 hours vs 1 hour. Methods: The serum asparaginase activity (SAA) levels from a phase 2, open label, single arm, multicenter, PK study following Erwinia treatment by IV infusion in ALL subjects (1-30 years old) with a previously documented hypersensitivity reaction (≥Grade 2) to pegaspargase were characterized by nonlinear mixed-effects modeling using NONMEM® software. The PPK model included data after 6 doses (1 cycle) of IV Erwinia administered over 1 hour at a 25,000 IU/m2 dose given on a Monday/Wednesday/Friday schedule. The PPK base model for IV Erwinia was identified by comparing different structural and error models. A stepwise approach with forward addition and backward elimination was used to identify important covariates. Visual predictive checks (VPC) were used to demonstrate PPK model predictability. Resampling of the original PK population was used to create a virtual patient population (n = 9999) to simulate average SAA levels and corresponding variability for both 1- and 2-hour IV infusion regimens, summarized by 95% prediction intervals. Results: The PK analysis set contained 24 subjects with 331 evaluable PK samples collected over 6 cycles of therapy. The majority of PK samples were collected during Cycle 1 (55%) with the majority of subjects being male (62.5%) and Caucasian (79%). The median (range) for age was 6.5 years (1-17) and for weight 21.4 kg (10.9 to 118.3). Trough SAA levels ≥0.1 IU/mL at 48 hours post dose 5 (primary endpoint) were achieved by 83% of the evaluable subjects in Cycle 1 (95% CI: 63%-95%). A 2-compartment model with inter-individual variability on clearance (CL) was found to best describe the PK of Erwinia. The final model for CL was: CL [mL/hr] = 123[mL/hr] + 17[mL/hr] * (weight [kg] / 21.4 kg) The central and peripheral volumes of distribution were 1.59 L and 0.154 L, respectively. As more PK samples were available for Cycle 1, separate proportional error models partitioned residual variability for Cycle 1 (36.6%) vs Cycles 2-6 (48.6%). The derived mean half-life estimate (CV%) was 7.51 hours (23.9%). The VPC demonstrated the bulk (>90%) of the observed SAA falling within the 95% PPK model-based simulation prediction intervals. The PPK model-based SAA simulation results after 1- and 2-hour IV infusions are displayed in Table 1 and Figure 1. Despite different initial rates of rise, similar SAA vs time profiles were observed when comparing 1- vs 2-hour infusion durations (Figure 1), with a similar number of subjects achieving therapeutic trough levels ≥ 0.1 IU/mL (Table 1). Conclusions: The final PPK model demonstrated a good ability to predict SAA allowing estimation of elimination characteristics and the application of subsequent model-based simulations.The PK simulations for 1- vs 2-hour IV Erwinia showed similar mean 48-hour trough SAA levels, as well as similar proportions of subjects having therapeutic 48-hour trough SAA ≥ 0.1 IU/mL. Based on these PK results, duration of IV Erwinia could be increased from 1 to 2 hours, which may reduce symptoms of infusion reactions. Reducing infusion reactions may potentially enablemore patients to complete Erwinia treatment. Upon approval from FDA in 2016, IV infusion duration in the Erwinaze USPI was revised from 1 hour to 1-2 hours; this is also consistent with the updated Children's Oncology Group protocols. Support: Jazz Pharmaceuticals. Disclosures Zomorodi: Jazz Pharmaceuticals: Employment, Equity Ownership. Dumas:Quintiles: Employment; Jazz Pharmaceuticals: Consultancy. Berry:Quintiles: Employment; Jazz Pharmaceuticals: Consultancy. Johnston:Jazz Pharmaceuticals: Consultancy; Quintiles: Employment. Eller:Jazz Pharmaceuticals: Employment, Equity Ownership.
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