Spreadsheet-Based Minimal Physiological Models for the Prediction of Clearance of Therapeutic Proteins in Pediatric Patients.

There is a growing interest in the use of physiologically based pharmacokinetic (PBPK) models as clinical pharmacology drug development tools. In PBPK modeling, not every organ or physiological parameter is required, leading to the development of a minimal PBPK (mPBPK) model, which is simple and efficient. The objective of this study was to streamline mPBPK modeling approaches and enable straightforward prediction of clearance of protein-based products in children. Four mPBPK models for scaling clearance from adult to children were developed and evaluated on Excel spreadsheets using (1) liver and kidneys; (2) liver, kidneys, and skin; (3) liver, kidneys, skin, and lymph; and (4) interstitial, lymph, and plasma volume. There were 35 therapeutic proteins with a total of 113 observations across different age groups (premature neonates to adolescents). For monoclonal and polyclonal antibodies, more than 90% of observations were within a 0.5- to 2-fold prediction error for all 4 methods. For nonantibodies, 79% to 100% of observations were within the 0.5- to 2-fold prediction error for the 4 different methods. Methods 1 and 4 provided the best results, >90% of the total observations were within the 0.5- to 2-fold prediction error for all 3 classes of protein-based products across a wide age range. The precision of clearance prediction was comparatively lower in children ≤2 years of age vs older children (>2 years of age) with methods 1 and 4 predicting 80% to 100% and 75% to 90% of observations within the 0.5- to 2-fold prediction error, respectively. The results of the study indicated that mPBPK models can be developed on spreadsheets, with acceptable performance for prediction of clearance.

Steady-State Serum IgG Trough Levels Are Adequate for Pharmacokinetic Assessment in Patients with Immunodeficiencies Receiving Subcutaneous Immune Globulin.

Patients with primary immunodeficiency diseases often require lifelong immunoglobulin (IG) therapy. Most clinical trials investigating IG therapies characterize serum immunoglobulin G (IgG) pharmacokinetic (PK) profiles by serially assessing serum IgG levels. This retrospective analysis evaluated whether steady-state serum IgG trough level measurement alone is adequate for PK assessment. Based on individual patient serum IgG trough levels from two pivotal trials (phase 2/3 European [NCT01412385] and North American [NCT01218438]) of weekly 20% subcutaneous IG (SCIG; Cuvitru, Ig20Gly), trough level-predicted IgG AUC (AUCτ,tp) were calculated and compared with the reported AUC calculated from serum IgG concentration-time profiles (AUCτ). In both studies, mean AUCτ,tp values for Ig20Gly were essentially equivalent to AUCτ with point estimates of geometric mean ratio (GMR) of AUCτ,tp/AUCτ near 1.0 and 90% CIs within 0.80-1.25. In contrast, for IVIG, 10%, mean AUCτ,tp values were lower than AUCτ by >20%, (GMR [90% CI]: 0.74 [0.70-0.78] and 0.77 [0.73-0.81] for the two studies, respectively). Mean AUCτ,tp values calculated for 4 other SCIG products (based on mean IgG trough levels reported in the literature/labels) were also essentially equivalent to the reported AUCτ (differences <10% for all except HyQvia, a facilitated SCIG product), while differences for IVIG products were >20%. In conclusion, steady-state serum IgG levels following weekly SCIG remain stable, allowing for reliable prediction of AUC over the dosing interval using trough IgG levels. These findings indicate that measuring steady-state serum IgG trough levels alone may be adequate for PK assessment of weekly SCIG.

Population pharmacokinetic modelling of intravenous immunoglobulin in patients with predominantly antibody deficiencies.

AIMS: There is considerable interpatient variability in the pharmacokinetics (PK) of intravenous immunoglobulin G (IVIG), causing difficulty in optimizing individual dosage regimen. This study aims to estimate the population PK parameters of IVIG and to investigate the impact of genetic polymorphism of the FcRn gene and clinical variability on the PK of IVIG in patients with predominantly antibody deficiencies. METHODS: Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed-effects modelling in Monolix®. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG. RESULTS: A total of 30 blood samples were analysed from 10 patients. The immunoglobulin G concentration data were best described by a one-compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient's individual weight. Goodness-of-fit plots indicated that the model fit the data adequately, with minor model mis-specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that 3-4-weekly dosing intervals were sufficient to maintain IgG levels of 5 g L-1 , with more frequent intervals needed to achieve higher trough levels. CONCLUSIONS: Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.

Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease.

Preclinical and clinical data support the use of focused ultrasound (FUS), in the presence of intravenously injected microbubbles, to safely and transiently increase the permeability of the blood-brain barrier (BBB). FUS-induced BBB permeability has been shown to enhance the bioavailability of administered intravenous therapeutics to the brain. Ideal therapeutics candidates for this mode of delivery are those capable of inducing benefits peripherally following intravenous injection and in the brain at FUS-targeted areas. In Alzheimer's disease, intravenous immunoglobulin (IVIg), a fractionated human blood product containing polyclonal antibodies, act as immunomodulator peripherally and centrally, and it can reduce amyloid pathology in the brain. Using the TgCRND8 mouse model of amyloidosis, we tested whether FUS can improve the delivery of IVIg, administered intravenously (0.4 g/kg), to the hippocampus and reach an effective dose to reduce amyloid plaque pathology and promote neurogenesis. Our results show that FUS-induced BBB permeability is required to deliver a significant amount of IVIg (489 ng/mg) to the targeted hippocampus of TgCRN8 mice. Two IVIg-FUS treatments, administered at days 1 and 8, significantly increased hippocampal neurogenesis by 4-, 3-, and 1.5-fold in comparison to saline, IVIg alone, and FUS alone, respectively. Amyloid plaque pathology was significantly reduced in all treatment groups: IVIg alone, FUS alone, and IVIg-FUS. Putative factors promoting neurogenesis in response to IVIg-FUS include the down-regulation of the proinflammatory cytokine TNF-α in the hippocampus. In summary, FUS was required to deliver an effective dose of IVIg to promote hippocampal neurogenesis and modulate the inflammatory milieu.

Efficacy of anti-influenza immunoglobulin (FLU-IGIV) in ferrets and mice infected with 2009 pandemic influenza virus.

Seasonal influenza causes significant morbidity and mortality around the world each year, even with the use of vaccines and antivirals. There is a need for more effective treatments for severe and hospitalized cases of influenza. In this study, we have tested the efficacy of a human plasma-derived IgG product (FLU-IGIV) against seasonal influenza in mouse and ferret models of influenza infection. FLU-IGIV successfully protected mice (100% survival) against lethal influenza infection. Also, the survival rate observed with FLU-IGIV treatment was better than the survival rate observed with oseltamivir (60% survival). FLU-IGIV significantly reduced the viral load in the lungs compared to placebo (PBS) in ferrets infected with influenza A/California/07/2009 (H1N1pdm09) virus. Overall, these studies demonstrate the efficacy of human plasma-derived FLU-IGIV in relevant animal models of influenza virus infection.

Population pharmacokinetics of immunoglobulin intravenous preparation in very low birth weight neonates.

BACKGROUND: Immunoglobulin products are widely used across multiple therapeutic areas such as immunodeficiency syndromes, infection and autoimmune diseases. The pharmacokinetics (PK) of immunoglobulins are well characterized in adults, but very little is known about the PK of immunoglobulins in neonates and infants (<2 years of age). OBJECTIVE: The objectives of the present study were: (1) characterize the PK of immunoglobulin intravenous preparation using model-independent (non-compartmental analysis), and (2) develop and evaluate a population PK model with extensive blood samples (8 blood samples) and sparse blood samples (2-3 blood samples). METHOD: Immunoglobulin G (IgG) concentration versus time data from very low birth weight neonates (n = 20) following intravenous administration were analyzed using nonlinear mixed effect modeling and non-compartmental approaches. Population pharmacokinetic models were developed from extensive and sparse sampling schemes. Models were evaluated based on the difference in objective function, goodness-of-fit plots and simulation based visual predictive check analysis. RESULTS: A non-compartmental analysis of IgG from neonates (bodyweight range 0.78-1.38 kg) indicated an average clearance of 3.0 ± 2.1 mL/day and volume of distribution at steady state 68 ± 25 mL. The population pharmacokinetic model from extensive sampling adequately described concentration- time data with mean clearance (2.7 mL/day), volume of central compartment (8.7 mL) and peripheral compartment (60 mL). The clearance and volume of distribution estimates using sparse sampling model (1 pre-and 2 post-dose blood samples) were comparable with extensive sampling. CONCLUSION: Our study provides important bridging data in scaling PK and dosing of immunoglobulins across a wide age range.

Pharmacometric Analysis of IgPro10 in Japanese and Non-Japanese Patients With Primary Immunodeficiency.

PURPOSE: Immunoglobulin (Ig) G replacement therapy, administered intravenously (IVIG) or subcutaneously (SCIG), is the standard treatment in patients with primary immunodeficiencies (PID). We aimed to characterize the pharmacokinetic (PK) characteristics of serum IgG following administration of IgPro10 every 3 or 4 weeks in Japanese patients with PID, and compare with PK in non-Japanese patients. A previously developed population PK (PPK) model was validated, and predicted parameters were compared with the results from the clinical study. METHODS: The previously developed PPK model, containing IgG concentration data from 5 non-Japanese studies, was supplemented with data from 3 Japanese studies of IgPro10 or IgPro20 to compare the IgG PK parameters between Japanese and non-Japanese patients. The model was externally validated by simulating IgG concentration-time profiles in Japanese patients to predict serum IgG PK characteristics and to compare them with observed Japanese PK data from Study IgPro10_3004. FINDINGS: The analysis included 4502 serum IgG concentration values (from 34 Japanese and 168 non-Japanese patients). PPK estimates from the current analysis demonstrated a clearance (CL) of 0.139 L/d, central volume (V2) of 4.01 L, inter-compartmental clearance (Q) of 0.30 L/d, and peripheral volume of 3.51 L. These results were consistent with those from the previously published PPK model, with similar bootstrap means and 95% CIs. Goodness-of-fit criteria indicated that the final PPK model was consistent with observed data, with no systemic bias in model prediction. Prediction-corrected visual predictive checks confirmed a good description of data on both SCIG and IVIG. PK parameters were equivalent between Japanese and non-Japanese patients. Body weight was determined to be a significant covariate on both CL and V2. Simulated and observed AUC and maximum and minimum serum IgG concentrations were similar, with 90% CIs overlapping between simulated and observed IgG concentrations in Japanese patients. IMPLICATIONS: PK parameter estimates of serum IgG were similar between Japanese and non-Japanese patients with PID. The PPK model, updated with Japanese data, was consistent with the previously published PPK model and could accurately predict both individual and population serum IgG concentration-time profiles following IgPro10 IV infusions every 3 or 4 weeks. EudraCT identifier: 2016-001631-12.

The Japanese experience and pharmacokinetics of antenatal maternal high-dose immunoglobulin treatment as a prophylaxis for neonatal hemochromatosis in siblings.

Background: Neonatal hemochromatosis (NH) is a rare but serious disease causing fulminant hepatic failure. The recurrence rate of NH in a subsequent infant of a mother with an affected infant is 70-90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) treatment has been reported to be effective for preventing NH recurrence. However, data on the IgG concentrations during this treatment are limited.Objective: We report a Japanese experience and present a pharmacokinetic simulation model of IgG during IVIG treatment.Methods: Women with histories of pregnancy diagnosed with NH were treated with IVIG weekly from the second trimester until the end of gestation. Serum IgG levels during treatment were collected frequently and pharmacokinetics were simulated by a two-compartment model.Results: Six women were included during eight pregnancies. None experienced severe adverse events. Three out of eight infants showed temporary liver dysfunction, but none required any treatment. A simulation study showed that the estimated trough and peak levels of IgG concentrations during IVIG were 2000-3000 and 4000-5000 mg/dl, respectively.Conclusion: This treatment prevented the recurrence of NH in siblings in Japanese women. We examined the details of serum IgG concentrations and introduced a new pharmacokinetic simulation model of IgG concentrations during IVIG treatment.

Is there a Role of Intravenous Immunoglobulin in Immunologic Recurrent Pregnancy Loss?

Recurrent pregnancy loss (RPL) commonly refers to three or more miscarriages that occur before 20 weeks of pregnancy. The immunological cause of RPL could be either an auto- or alloimmune-related event or both. Because of the discovery of immunological abnormalities in RPL patients in clinical practice, several immunomodulatory therapies were introduced to maintain the immune balance at the maternal-fetal interface. Intravenous immunoglobulin (IVIg) is one of the immunomodulators. In recent years, several studies have analyzed the therapeutic effect of IVIg on RPL patients with antiphospholipid syndrome (APS) or unexplained RPL. However, their results are controversial. IVIg can be used in RPL patients with APS who have previously failed in other treatments. It is recommended that IVIg infusion could be considered used before conception in RPL patients who have cellular immune abnormalities such as increased natural killer (NK) cell counts, NK cell cytotoxicity, or increased T helper (Th)1/Th2 ratio, depending on the cut-off values of each hospital. The aim of this review was to summarize the mechanisms, efficacy, pharmacokinetics, and side effects associated with passive immunization using IVIg in immunologic RPL, according to the literature published in recent years. We hope that more obstetricians will be able to understand the timing and indication of IVIg properly in immunologic RPL patients and effectively enhance pregnancy outcomes for mothers and neonates.

Immunoglobulin administration for the treatment of CIDP: IVIG or SCIG?

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired neurological disorder characterized clinically by weakness and impaired sensory function evolving over 2 months or more, loss or significant decrease in deep tendon reflexes, and by electrophysiological evidence of peripheral nerve demyelination. Expeditious diagnosis and treatment of CIDP early in the disease course is critical such that irreversible disability can be avoided. Intravenous immunoglobulin (IVIG) is one first-line and maintenance therapy option for CIDP. The US Food & Drug Administration's (FDA's) approval of subcutaneous immunoglobulin (SCIG) in 2018 provides patients with CIDP more treatment options for maintenance therapy. The different options for administration of IG treatment create the need for information to assist clinicians and patients in choosing the optimal therapeutic approach. Considerations for pharmacokinetics, administration procedures, adverse events, patient variables, and cost will all be discussed in this article.

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants.

An understanding of pediatric pharmacokinetics (PK) is essential for first-in-pediatric dose selection and clinical trial design. At present, there is no reliable way to scale the PK of monoclonal antibodies and immunoglobulin G drug products from adults to young children or to premature infants-a vulnerable population with a rapidly growing drug development pipeline. In this work, pediatric physiologically based PK models are constructed in PK-Sim and Mobi to explore the PK of pagibaximab, palivizumab, MEDI8897, and intravenous immunoglobulin in preterm infants. In addition to considering ontogeny in pediatric organ volumes, organ composition, blood flow rates, and hematocrit, advanced ontogeny is applied for 3 key parameters: capillary surface area, hematopoietic cell concentration, and lymph flow rate. The role and importance of each parameter for determining pediatric clearance (CL) and volume of distribution at steady state (VSS ) are quantitatively assessed with a local sensitivity analysis. In addition, the uncertainty around parameters with limited information in pediatrics is addressed (eg, free neonatal Fc receptor concentration). The full ontogeny parameterization yields pediatric PK predictions that are within 1.5-fold prediction error >90% of the time for preterm infants, with an absolute average fold error of 1.05. This result suggests that many of the key factors related to ontogeny are appropriately addressed. Overall, this study makes a first step toward developing a platform pediatric physiologically based PK model for monoclonal antibodies and immunoglobulin G drug products by solidifying existing parameterizations, integrating new concepts, and drawing attention to unmet needs for physiologic knowledge in children.

Pharmacokinetic properties of Privigen® in Japanese patients with primary immunodeficiency.

This prospective, Phase 3, open-label, study (EudraCT: 2016-001631-12) evaluated pharmacokinetic (PK) characteristics of 3-/4-weekly Privigen® (IgPro10, CSL Behring, King of Prussia, PA, USA) in Japanese patients with PID. PK parameters including serum trough immunoglobulin (IgG) level before next infusion during the wash-in/wash-out phase (Ctrough), area under the concentration-time curve from time point zero to the last time point with quantifiable concentration (AUC0-last), dose-adjusted AUC0-last (dAUC), lowest and highest observed IgG levels (Cmin, Cmax), time to reach Cmax (Tmax), and total clearance (CL) were analyzed for both regimens of Privigen® (dose: 138-554 mg/kg body weight). Ten patients were included in this analysis (3-/4-weekly: n = 2/n = 8). Ctrough levels achieved ranged 7.96-10.05 g/L. Cmax was observed approximately 1 h after the start of the infusion in both regimens. Mean (SD [not applicable for 3-weekly data]) PK parameters: Cmax, 16.60 and 14.20 (5.53) g/L; Cmin, 10.60 and 8.53 (3.89) g/L; AUC0-last, 5971 and 6591 (2633) g*h/L; dAUC, 0.41 and 0.46 (0.19) g*h/L/mg; CL, 2.53 and 2.53 (1.00) mL/h and median Tmax was 1.19 and 1.14 h, for 3-/4-weekly dosing regimens, respectively. Privigen® PK characteristics in Japanese patients were similar between dosing regimens and to previously-reported results in non-Japanese patients with PID.

Immune globulin subcutaneous, human - klhw 20% for primary humoral immunodeficiency: an open-label, Phase III study.

Aim: This prospective, Phase III study assessed the pharmacokinetics (PK), safety and tolerability of immune globulin subcutaneous, human - klhw 20% solution (IGSC-C 20%) in participants with primary humoral immunodeficiency (PI), compared with immune globulin injection (human), 10% caprylate/chromatography purified (IGIV-C 10%). Patients & methods: About 53 participants enrolled. Total 44 received IGIV-C 10% in the run-in phase and then entered the IV phase (with an additional nine who were already receiving IGIV-C 10% and entered the IV phase directly) for steady-state IV PK assessments. Total 49 entered the SC phase (weekly doses of IGSC-C 20% for ∼24 weeks). The PK profiles of IGIV-C 10% and IGSC-C 20% and their safety and tolerability parameters were compared. Results: At a dose adjustment factor of 1.37, IGSC-C 20% provided comparable (noninferior and bioequivalent) overall total immunoglobulin G exposure to IGIV-C 10% over an equal time interval. About 33 participants reported 79 adverse events during run-in + IV phases; 41 participants reported 141 adverse events during the SC phase, with most being local infusion site reactions. The majority of infusion site reactions were mild to moderate in severity. Conclusion: IGSC-C 20% was bioequivalent to IGIV-C 10% and was well tolerated, with a safety profile comparable with IGIV-C 10%, in this study. Trial registration: ClinicalTrials.gov identifier: NCT02604810.

Optimization of intravenous immune globulin use at a comprehensive cancer center.

PURPOSE: Intravenous immune globulin (IVIG) is a high-cost medication used in a diverse range of settings. At many institutions, IVIG is dosed using total body weight (TBW). Recent evidence suggests that alternative dosing weights reduce waste without compromising clinical outcomes. The objective of this study was to quantify the waste reduction potential generated through the use of alternative IVIG dosing weights. METHODS: We performed a retrospective analysis of all IVIG doses administered from January 2011 through January 2016 to adults (≥18 years). TBW and height at the time of administration were used to calculate prescribed dose (g/kg), ideal body weight (IBW), and adjusted body weight (AdjBW). Three dosing methods were analyzed, as follows: use of AdjBW if TBW is >120% IBW (method 1), AdjBW for all doses (method 2), and IBW for all doses (method 3). Outcomes included potential IVIG use averted, direct drug cost savings, and reductions in outpatient infusion times for each method. RESULTS: A total of 9,918 doses were administered to 2,564 patients over 5 years, representing an average usage of 75,994 g/year. If dosing methods 1, 2, and 3 had been used, the annual use of IVIG would have decreased by 21.9% (16,658 g/year, p < 0.001), 24.2% (18,371 g/year, p < 0.001), and 35.9% (27,252 g/year, p < 0.001), respectively. This translates into average annual cost differences of $2.37 million, $2.62 million, and $3.89 million and average annual outpatient infusion time savings of 841 hours, 920 hours, and 1,366 hours, respectively. CONCLUSION: IVIG dosing optimization through use of alternative dosing weights represents a significant source of waste reduction and cost reduction.

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.

Clinical Efficacy, Safety and Tolerability of a New Subcutaneous Immunoglobulin 16.5% (Octanorm [Cutaquig®]) in the Treatment of Patients With Primary Immunodeficiencies.

Introduction: Subcutaneously administered immunoglobulin (SCIG) is increasingly used to treat patients with primary immunodeficiencies (PIDs). Octanorm (marketed as cutaquig® in USA and Canada) is a new 16.5% solution of human SCIG, manufactured by a process based on that of the intravenous preparation (IVIG) octagam®. Objectives: To investigate the efficacy, safety and tolerability of octanorm in a prospective, open-label, single-arm phase 3 study involving adult and pediatric patients with PIDs (NCT01888484; clinicaltrials.gov/ct2/show/NCT01888484). Methods: Patients who were previously treated with IVIG received a total of 64 weekly SCIG infusions, including 12 weekly infusions during the wash-in/wash-out period, followed by 52 weekly infusions during the evaluation period. Results: A total of 61 patients aged 2-73 years received 3,497 infusions of octanorm. The mean dose per patient was 0.175 g/kg/infusion. The mean calculated dose conversion factor from the patients' previous IVIG dose for octanorm was 1.37. No serious bacterial infections developed during the study. The rate of other infections per person-year during the primary observation period was 3.43 (upper 95% CI 4.57). All but one non-bacterial infection were mild or moderate in intensity. IgG trough levels were constant during the course of the study. Eleven patients (18.0%) experienced 14 mild or moderate systemic adverse events (AEs) related to octanorm. The rate of related AEs per infusion was 0.004. In 76.7% of infusions, no infusion site reactions were observed and only two (0.3%) reactions were deemed severe. The incidence of site reactions decreased with successive infusions. Conclusion: The new 16.5% SCIG octanorm was shown to be efficacious in preventing infections in PIDs, and was well tolerated.

Phase 1 study of PSMA ADC, an antibody-drug conjugate targeting prostate-specific membrane antigen, in chemotherapy-refractory prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer. METHODS: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging. RESULTS: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent. CONCLUSIONS: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.

Privigen® has similar pharmacokinetic properties in primary and secondary immune deficiency.

PURPOSE: Primary (PID) and secondary immune deficiencies (SID) represent diverse groups of diagnoses, yet both can be effectively treated with intravenous immunoglobulin (IVIG) replacement therapy. Guidelines for the use of IVIG in SID vary due to the paucity of data. The objective was to analyze available IVIG Privigen® (IgPro10, CSL Behring, Bern, Switzerland) data on Efficiency Index (EI) and pharmacokinetic (PK) parameters in patients with PID and SID. METHODS: Three Privigen® studies (NCT00168025, NCT00322556, and the observational study IgPro10_5001) were used to identify patients with PID and SID meeting the qualifying criteria for the PK analysis. PK properties of IVIG were estimated using a population PK model based on a standard two-compartment PK model. Immunoglobulin G (IgG) EI was calculated as the gain in serum IgG level per unit external IgG dose. RESULTS: A similar IVIG dose-serum IgG concentration relationship was observed in patients with PID (N = 90) and SID (N = 91). IgG EI was inversely proportional to the endogenous IgG concentration and comparable in PID (slope = -1.079) and SID (slope = -2.12). CONCLUSIONS: These findings indicate that the disposition of Privigen® is similar during IgG replacement therapy in PID and SID. The results contribute to the understanding of IVIG treatment of SID and may support an evidence-based approach for the use of IVIG in SID in the future.

Application of Physiologically Based Pharmacokinetic Modeling to Predict the Effects of FcRn Inhibitors in Mice, Rats, and Monkeys.

There is a growing interest in developing inhibitors of the neonatal Fc-receptor, FcRn, for use in the treatment for humoral autoimmune conditions. We have developed a new physiologically based pharmacokinetic model that is capable of characterizing the pharmacokinetics and pharmacodynamics of anti-FcRn monoclonal antibodies (mAb) in mice, rats, and monkeys. The model includes incorporation of FcRn recycling of immune gamma globulin (IgG) in hematopoietic cells in addition to FcRn recycling of IgG in vascular endothelial cells and considers FcRn turnover and intracellular cycling. The model captured antibody disposition in wild-type and FcRn-knockout mice and rats, and also predicted the effects of intravenous immune globulin and anti-FcRn mAb on IgG disposition. Simulations predicted the change in IgG clearance in response to intravenous immune globulin with good accuracy in rats (mean prediction error of 7.15% ± 7.67%). In monkeys, prediction windows for simulated IgG concentration versus time data, as generated through Monte Carlo simulation, were able to capture the effects of anti-FcRn mAb on endogenous IgG. The model may have utility in guiding preclinical evaluations of anti-FcRn therapies in development, potentially assisting in the identification of optimal dosing strategies for this emerging class of immunosuppressive drugs.

Personalized Therapy: Immunoglobulin Replacement for Antibody Deficiency.

Immunoglobulin replacement therapy is the cornerstone of management for most primary immunodeficiency disease patients. The selection of a particular product, dose, and route of administration requires an understanding of the features of therapeutic immunoglobulin as well as patient-specific risk factors in order to maximize efficacy and tolerability and minimize risk. Individualizing therapy, taking into consideration the burdens of care, is necessary in order to optimize patient outcomes.