Publications by authors named "Rudy Gunawan"

8 Publications

  • Page 1 of 1

Lack of QT Prolongation for 2'-O-Methoxyethyl-Modified Antisense Oligonucleotides Based on Retrospective Exposure/Response Analysis of Ten Phase 1 Dose-Escalation Placebo-Controlled Studies in Healthy Subjects.

Nucleic Acid Ther 2017 Oct 11;27(5):285-294. Epub 2017 Aug 11.

1 Department of Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Inc. , Carlsbad, California.

The potential of QT prolongation of ten 2'-O-methoxyethyl-modified (2'-MOE) antisense oligonucleotides (ASOs) was evaluated retrospectively via exposure/response (ER) analysis using data from Phase 1 clinical studies in healthy subjects. All Phase 1 studies were double-blind, placebo-controlled, single and multiple ascending dose studies designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of the ASOs in healthy subjects. The active doses in these studies ranged from 50 to 450 mg administered by subcutaneous (SC) injection in single and multiple ascending dose cohorts. Two of the ten studies also included 2-h intravenous (IV) infusions up to 600 mg. Electrocardiogram (ECG) measurements were performed at baseline and selected time points (including T). The correlation between QTcF intervals corrected for baseline (ΔQTcF) and the mean time-matched placebo (ΔΔQTcF) with PK plasma exposure when available was evaluated using a linear mixed-effects approach. There was no evidence for QTc prolongation associated with increasing plasma concentrations in healthy subjects, including exposures with treatment up to 450 mg administered SC or 600 mg by IV infusions, and concentrations that are 4-20 times the C of the therapeutic dose, as assessed by both ΔQTcF and ΔΔQTcF. The ER analysis of the relationship between drug plasma concentration and ΔΔQTcF showed that the slope of the regression line was close to zero, and the upper bound of the 90% confidence interval at twice the mean observed (or predicted) C (2 × C) of the clinical therapeutic dose (ie, the highest clinically relevant plasma concentration) was well below 10 ms for all 10 compounds evaluated. Therefore, no concentration-dependent effect on QT prolongation was observed for any one of the ten 2'-MOE ASOs evaluated in Phase 1 studies. These results confirmed that 2'-MOE ASOs, as a chemical class, do not cause QT prolongation at clinically relevant dose levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/nat.2017.0676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649121PMC
October 2017

Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations.

J Clin Pharmacol 2017 08 29;57(8):1031-1041. Epub 2017 Mar 29.

Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Carlsbad, CA, USA.

Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Q = 0.572 L/h, Q = 0.069 L/h, CL = 2.50 L/h, CL = 0.133 L/hr, V = 0.441 L, V = 32.0 L, V = 429 L, and V = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on V , V , and CL . The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.884DOI Listing
August 2017

Disposition and Pharmacokinetics of a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Human Lipoprotein (a) in Monkeys.

Nucleic Acid Ther 2016 12 8;26(6):372-380. Epub 2016 Aug 8.

Ionis Pharmaceuticals, Inc. , Carlsbad, California.

Triantennary N-acetyl galactosamine (GalNAc)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency due to receptor-mediated uptake into hepatocyte. The disposition and pharmacokinetics of ISIS 681257, a GalNAc-conjugated ASO, were studied in monkeys. Following subcutaneous (SC) injection, ISIS 681257 was rapidly absorbed into the systemic circulation, with peak plasma levels observed within hours after dosing. After reaching C, plasma concentrations rapidly declined in a multiexponential manner and were characterized by a dominant initial rapid distribution phase in which drug transferred to tissues from circulation, followed by a much slower terminal elimination phase (half-life of 4 weeks). Intact ISIS 681257 is the major full-length oligonucleotide species in plasma (≥70%). In tissues, the conjugated-GalNAc sugar moiety was rapidly metabolized, leaving the fully unconjugated form as the only full-length oligonucleotide detected at 48 h after dosing. Unconjugated ISIS 681257 cleared slowly from tissues with a half-life of 4 weeks. ISIS 681257 was highly bound to plasma proteins (>97% bound), which limited its urinary excretion. Disposition of ISIS 681257 in plasma and liver appeared nonlinear over the 1-40 mg/kg dose range studied. The plasma and liver tissue concentration data were well described by a population based mixed-effects modeling approach with Michaelis-Menten uptake from plasma to liver. Safety data from the study and the good exposure, as well as the extended half-life of the unconjugated ASO in the liver, support further development and less frequent dosing in Phase I clinical study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/nat.2016.0623DOI Listing
December 2016

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy.

Cancer Chemother Pharmacol 2016 Feb 20;77(2):405-12. Epub 2016 Jan 20.

United Therapeutics Corporation, 55 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.

Purpose: Dinutuximab (Unituxin™; ch14.18), a monoclonal antibody against disialoganglioside, improved survival as part of post-consolidation therapy for high-risk neuroblastoma. United Therapeutics Corporation (UTC) assumed ch14.18 production from the National Cancer Institute (NCI); this study evaluates pharmacokinetic comparability, safety, and tolerability of UTC and NCI products.

Methods: In this randomized, two-sequence crossover study, 28 patients aged ≤8 years with high-risk neuroblastoma received equivalent ch14.18-UTC or ch14.18-NCI doses. Despite comparable protein content, nominal doses differed: 17.5 mg/m(2)/day (ch14.18-UTC) and 25 mg/m(2)/day (ch14.18-NCI). Patients received one product during therapy cycles 1 and 2, the other during cycles 3-5. Ch14.18 pharmacokinetic profile characterization used population modeling (NONMEM(®) version 7.2). A two-compartment model with first-order distribution and elimination processes described pharmacokinetic data. Estimated product parameters were normalized to UTC nominal dose. For pharmacokinetic comparability, the final model was used to estimate exposure ratios (UTC/NCI) and associated 90 % confidence intervals (CIs) for area under the curve from time zero to infinity (AUCinf) and maximum concentration (C max). All comparisons were based on a standardized single-dose regimen (17.5 mg/m(2) over 10 h).

Results: Final-model pharmacokinetic parameters were similar to previously published ch14.18-NCI parameters and comparable for UTC and NCI products. Products' systemic exposures were comparable, with 90 % CIs around ratios for AUCinf (0.96; 90 % CI 0.88-1.04) and C max (1.04; 90 % CI 0.98-1.11) within standard bioequivalence bounds (90 % CI 0.80-1.25). Products' adverse events were similar and consistent with those previously reported.

Conclusions: Equivalent actual ch14.18-UTC and ch14.18-NCI doses produced comparable exposures, with no notable safety or tolerability differences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-015-2955-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747995PMC
February 2016

No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

Eur J Clin Pharmacol 2016 Mar 9;72(3):267-75. Epub 2015 Dec 9.

Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA.

Purpose: The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects.

Methods: In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis.

Results: In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively.

Conclusions: Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00228-015-1992-yDOI Listing
March 2016

Dose response of umeclidinium administered once or twice daily in patients with COPD: a pooled analysis of two randomized, double-blind, placebo-controlled studies.

J Clin Pharmacol 2014 Nov 24;54(11):1214-20. Epub 2014 Jun 24.

Department of Medicine, University of North Carolina, North Carolina, USA.

Umeclidinium (UMEC) is an inhaled long-acting muscarinic antagonist approved in the US and EU for the once-daily (QD) treatment of chronic obstructive pulmonary disease (COPD); it is not indicated for the treatment of asthma. To fully characterize the dose-response relationship of UMEC in patients with COPD, a pooled analysis of data from two randomized, placebo-controlled, cross-over, dose-ranging studies was performed, evaluating UMEC at doses of 15.6-1000 mcg QD and 15.6-250 mcg twice daily (BID). The primary endpoint was trough forced expiratory volume in one second (FEV(1)) at the end of each study's treatment period (Day 8/Day 15). A population model-based analysis using total daily UMEC dose was used for the primary analysis comparing QD and BID dosing. A physiological effect (E(max)) model was optimal in defining the relationship between UMEC dose and the primary endpoint, demonstrating a clear monotonic dose response over QD and BID dosing regimens. UMEC doses ≥62.5 mcg QD were differentiated from lower doses and BID dosing did not provide benefit over QD dosing. The potency (ED(50)) estimate was 33 mcg with QD dosing. These data indicate that UMEC 62.5 mcg and 125 mcg QD provide lung function benefits that warrant further investigation for the treatment of COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcph.340DOI Listing
November 2014

A multi-route model of nicotine-cotinine pharmacokinetics, pharmacodynamics and brain nicotinic acetylcholine receptor binding in humans.

Regul Toxicol Pharmacol 2013 Feb 23;65(1):12-28. Epub 2012 Oct 23.

Battelle, Pacific Northwest Division, 902 Battelle Blvd., Richland, WA 99352, USA.

The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yrtph.2012.10.007DOI Listing
February 2013

Twenty-four hour human urine and serum profiles of bisphenol a during high-dietary exposure.

Toxicol Sci 2011 Sep 24;123(1):48-57. Epub 2011 Jun 24.

Fundamental and Computational Sciences, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.

By virtue of its binding to steroid hormone receptors, bisphenol A (BPA, the unconjugated bioactive monomer) is hypothesized to be estrogenic when present in sufficient quantities in the body, raising concerns that widespread exposure to BPA may impact human health. To better understand the internal exposure of adult humans to BPA and the relationship between the serum and urinary pharmacokinetics of BPA, a clinical exposure study was conducted. Blood and urine samples were collected approximately hourly over a 24-h period from 20 adult volunteers who ingested 100% of one of three specified meals comprising standard grocery store food items for breakfast, lunch, and dinner. The volunteers' average consumption of BPA, estimated from the urinary excretion of total BPA ((TOT)BPA = conjugated BPA + BPA), was 0.27 μg/kg body weight (range, 0.03-0.86), 21% greater than the 95th percentile of aggregate exposure in the adult U.S. population. A serum time course of (TOT)BPA was observable only in individuals with exposures 1.3-3.9 times higher than the 95th percentile of aggregate U.S. exposure. The (TOT)BPA urine concentration T(max) was 2.75 h (range, 0.75-5.75 h) post-meal, lagging the serum concentration T(max) by ∼1 h. Serum (TOT)BPA area under the curve per unit BPA exposure was between 21.5 and 79.0 nM•h•kg/μg BPA. Serum (TOT)BPA concentrations ranged from less than or equal to limit of detection (LOD, 1.3 nM) to 5.7 nM and were, on average, 42 times lower than urine concentrations. During these high dietary exposures, (TOT)BPA concentrations in serum were undetectable in 83% of the 320 samples collected and BPA concentrations were determined to be less than or equal to LOD in all samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfr160DOI Listing
September 2011