Population pharmacokinetic simulation of varied Immune Globulin Subcutaneous (Human), 20% solution (Ig20Gly) loading and maintenance dosing regimens in immunoglobulin-naïve patients with primary immunodeficiency diseases.

BACKGROUND: The pharmacokinetics of Ig20Gly, a 20% subcutaneous immunoglobulin (IG) therapy, is well characterized in IG-experienced patients with primary immunodeficiency diseases (PID). Data from IG-naïve patients are limited. OBJECTIVE: Simulate serum total immunoglobulin G (IgG) pharmacokinetic profiles in IG-naïve patients with PID for different Ig20Gly initiation and maintenance dosing regimens. METHODS: A population pharmacokinetic model developed with data from pivotal phase 2/3 trials of weekly Ig20Gly in PID (NCT01412385, NCT01218438) was used to simulate pharmacokinetic profiles of IgG in various scenarios with 400- or 800-mg/kg total loading doses (administered as split doses over 1-2 weeks) and corresponding 100- or 200-mg/kg weekly maintenance doses, respectively. Endogenous baseline IgG levels (1.5, 2.0, 4.0, 6.0 g/L) were evaluated for each scenario; time to putative therapeutic target IgG trough level (7 g/L) was determined. RESULTS: Serum IgG levels reached steady-state by approximately Week 12 for all scenarios and baseline endogenous IgG levels. Time to target trough level generally occurred sooner with 1-week versus 2-week loading schemes. Endogenous baseline IgG levels <4 g/L required a 1-week 800-mg/kg total loading dose to achieve target levels within 2 weeks. Both maintenance regimens sustained serum IgG above target level. CONCLUSIONS: Simulations indicated IG-naïve patients with PID can achieve protective serum IgG levels within 1-3 weeks using appropriate Ig20Gly loading regimens. Patients with low endogenous IgG may benefit most from an 800-mg/kg/month loading dose. 400- or 800-mg/kg/month Ig20Gly maintenance regimens appeared adequate to maintain stable IgG levels. Serum IgG monitoring and clinical status can guide dosing parameters.

Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP-458).

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/m2 (N = 6) and 25 mg/m2 (N = 6), and intravenous (IV) data at 25 mg/m2 (N = 6) and 37.5 mg/m2 (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/m2 , and in 80.9% of adult and 94.5% of pediatric populations receiving IV administration at 37.5 mg/m2 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/m2 IM or 37.5 mg/m2 IV on a M/W/F dosing schedule in pediatric and adult patients.

Population pharmacokinetic modeling and simulation of immunoglobulin exposure with varying dosing intervals of subcutaneous immunoglobulin 20% (Ig20Gly) in patients with primary immunodeficiency diseases.

BACKGROUND: Immunoglobulin (IG) replacement therapy in patients with primary immunodeficiency diseases (PID) can be administered daily to every 2 weeks subcutaneously (SCIG) or every 3 or 4 weeks intravenously (IVIG). OBJECTIVES: Develop a population pharmacokinetic (PK) model simulating IG exposure with Ig20Gly, a 20% SCIG; determine the dose adjustment factor for Ig20Gly relative to IVIG. METHODS: Data from patients with PID treated with Ig20Gly and IVIG 10% were used to characterize IG population PK by nonlinear mixed-effects modeling and validated using data splitting and a visual predictive check. IG profiles were simulated for 1000 patients/interval treated with Ig20Gly (daily, every 2 days, every 3 days, twice weekly, weekly, every 2 weeks). An Ig20Gly adjustment factor of 130% was used to simulate Ig20Gly to IVIG AUC ratios for weekly or every 2 weeks Ig20Gly dosing intervals and a monthly IVIG dosing interval. RESULTS: A 1-compartment model, using weight as a covariate on clearance, derived from an index modeling dataset (n = 81) demonstrated predictability for a validation dataset (n = 21). The model estimate of bioavailability was 73.9%. Simulations for 6 dosing intervals showed similar mean profiles with overlapping prediction intervals. Mean AUC ratios of Ig20Gly to IVIG with a dose adjustment factor of 1.30:1 were 98.7% for weekly and 97.7% for twice-weekly administration demonstrating comparable exposure. CONCLUSION: Ig20Gly exposures from daily to up to every 2 weeks appeared equivalent. A 1.30 conversion factor provided coverage comparable to IVIG when Ig20Gly is administered daily to every 2 weeks.

Pharmacokinetics and metabolic profile of free, conjugated, and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract.

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(0-->infinity) values of the conjugated silymarin flavonolignans were 4- to 30-fold higher than those of their free fractions, with SB(B) (mean AUC(0-->infinity) = 51 and 597 microg x h/l for free and conjugated, respectively) and ISB(A) (mean AUC(0-->infinity) = 30 and 734 microg x h/l for free and conjugated, respectively) exhibiting higher AUC(0-->infinity) 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.

Warfarin dosing and the promise of pharmacogenomics.

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.