Keith Nieforth
Hoffmann-La Roche
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Featured researches published by Keith Nieforth.
Transplantation | 1997
Flavio Vincenti; Marianne Lantz; Jytte Birnbaum; Marvin R. Garovoy; Diane R. Mould; John Hakimi; Keith Nieforth; Susan Light
The efficacy of murine monoclonal anti-interleukin 2 alpha chain receptor (Tac) antibodies is limited by a short half-life and the development of antibodies to the heterologous protein. The safety, pharmacokinetics-dynamics, and immunosuppressive effect of a humanized anti-Tac antibody (HAT) was evaluated in 12 renal transplant recipients. Ten patients received living related transplants (three HLA-identical matches and seven one-haplotype or zero-haplotype matches) and two patients received cadaver organs. The patients were divided into four HAT treatment arms: 0.5 mg/kg/week (n=4), 1 mg/kg/week (n=2), 0.5 mg/kg every other week (n=3), and 1 mg/kg every other week (n=3). The first dose of HAT was given within 12 hr before transplantation, and four additional doses were given after transplantation. Patients were also placed on cyclosporine, steroids, and azathioprine. Only one patient, a recipient of a cadaver kidney in the lowest HAT treatment arm, had a reversible rejection episode. The 10 recipients of living related transplants were compared with 17 historical controls treated with an identical immunosuppressive regimen except for HAT. Whereas none of the HAT-treated living related donor recipients had a rejection episode, 6 of 17 (41%) of the historical controls had a rejection episode in the first year after transplantation. There were no first-dose reactions after HAT therapy or other subsequent side effects. None of the patients experienced opportunistic infections or malignancies. One patient developed low-titer anti-HAT antibodies, although the patient maintained high serum HAT concentrations throughout the study. Immune monitoring showed that there were no changes in the percentage or absolute counts of CD3 cells or T-cell subsets after HAT therapy. However, there was a significant decrease in the number of circulating lymphocytes that expressed free Tac. The overall harmonic mean half-life of HAT was 273 hr. The results of this study indicate that HAT given at 1 mg/kg every other week for a total of five doses may provide therapeutic HAT concentration levels and result in good saturation of Tac receptors for at least 12 weeks after transplantation. In summary, HAT is safe and is well tolerated by patients. Its long half-life and lack of immunization could make it a very useful immunosuppressive drug.
Clinical Pharmacology & Therapeutics | 1996
Keith Nieforth; Rosemary Nadeau; Indravadan H. Patel; Diane R. Mould
Interferon alfa‐2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half‐life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG‐modified interferon alfa‐2a showed a greater than twofold increase in the circulating half‐life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa‐2a or PEG‐interferon alfa‐2a in healthy volunteers. Analysis of the pharmacokinetic‐pharmacodynamic relationship suggested that the PEG‐modified interferon alfa‐2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.
Clinical Pharmacokinectics | 2005
Indravadan H. Patel; Xiaoping Zhang; Keith Nieforth; Miklos Salgo; Neil Buss
AbstractEnfuvirtide, the first fusion inhibitor approved for the treatment of HIV-1 infection, is a synthetic peptide that binds to HIV-1 glycoprotein 41, blocking the fusion of viral and cellular membranes. When administered subcutaneously at the recommended dose of 90mg twice daily with optimised background antiretroviral therapy, enfuvirtide significantly reduces plasma HIV-1 RNA levels up to 48 weeks compared with optimised background therapy alone.Enfuvirtide exhibits a small volume of distribution (5.48L), low systemic clearance (1.4 L/h) and high plasma protein binding (92%). Less than 17% of enfuvirtide is converted to a minimally active deaminated form of the parent drug. Both enfuvirtide and its metabolite are primarily eliminated via catabolism to amino acid residues. Following subcutaneous administration, enfuvirtide is almost completely absorbed, and exposure increases almost linearly with dose over the range 45–180mg.When administered at the recommended dose in adults, subcutaneous absorption is slow and protracted, resulting in relatively flat steady-state plasma concentration-time profiles. Bioavailability is high (84.3%) and the elimination half-life (3.8 hours) supports twice-daily administration. Comparable absorption was observed from three different anatomical injection sites. The pharmacokinetic-pharmacodynamic relationship indicates that the recommended dose, in combination with other active antiretrovirals, is optimal. Enfuvirtide clearance is influenced to a small extent by sex and bodyweight but this does not necessitate dosage adjustment. In vitro and in vivo studies indicate that enfuvirtide has a low potential to interact with concomitantly administered drugs. Enfuvirtide did not influence concentrations of drugs metabolised by cytochrome P450 (CYP) 3A4, CYP2D6 or N-acetyltransferase, and had only minimal effects on those metabolised by CYP1A2, CYP2E1 or CYP2C19. Coadministration of ritonavir, ritonavir-boosted saquinavir or rifampicin (rifampin) did not result in clinically significant changes in enfuvirtide pharmacokinetics.In HIV-1-infected paediatric patients, subcutaneous dosages based on bodyweight (2 mg/kg twice daily) produce pharmacokinetics broadly similar to those observed in adults administered 90mg twice daily.
The Journal of Clinical Pharmacology | 2003
Mark A. Boyd; Xiaoping Zhang; Albert Dorr; Kiat Ruxrungtham; Stanley J. Kolis; Keith Nieforth; Tosca Kinchelow; Neil Buss; Indravadan H. Patel
The primary objective was to determine whether rifampicin influences the pharmacokinetics of enfuvirtide in HIV‐1‐infected patients. In a single‐center, open‐label, one‐sequence crossover, clinical pharmacology study, 12 HIV‐1‐infected adults received enfuvirtide (90 mg, twice daily) on days 1 to 3 and days 11 to 13 (morning dose only on days 3 and 13) and rifampicin (600 mg, once daily) from days 4 to 13. Plasma concentrations were measured for enfuvirtide and its metabolite (days 3 and 13) and rifampicin (day 13 only). The ratios of least squares means (LSM) and 90% confidence intervals for enfuvirtide and enfuvirtide metabolite pharmacokinetic parameters (AUC12h, Cmax, Ctrough) were estimated in the presence and absence of rifampicin. Treatments were compared using an analysis of variance for natural log‐transformed variables, with factors patient and treatment. Efficacy and safety were also monitored. Steady‐state rifampicin had no appreciable effect on any of the pharmacokinetic parameters assessed for either enfuvirtide or its metabolite. The ratio of LSM for AUC12h, Cmax, and Ctrough for enfuvirtide was 97.5%, 103%, and 84.9%, respectively, and 108%, 112%, and 92.9%, for the enfuvirtide metabolite. Rifampicin did not affect the t1/2 of enfuvirtide or its metabolite. There were no unexpected effects of rifampicin on the short‐term antiviral effect or safety of the administered antiretroviral treatment. The pharmacokinetics of enfuvirtide are not induced by a 10‐day pretreatment with rifampicin.
Expert Opinion on Investigational Drugs | 2001
Stefan Zeuzem; Jenny E Heathcote; Nancy Martin; Keith Nieforth; Marlene W. Modi
Current therapy for hepatitis C remains far from optimal. The modification of IFN by the attachment of a polyethylene glycol (PEG) moiety has produced long-lasting IFNs. A 40 kDa branched peginterferon alfa-2a (40 kDa) (PEG-IFN alfa-2a) has unique pharmacokinetic and pharmacodynamic properties. PEG-IFN alfa-2a is absorbed in a sustained manner and its clearance is reduced substantially compared with IFN alfa-2a, resulting in sustained serum drug concentrations. These constant serum drug levels stay above the EC50 values (effective concentration 50%) needed for antiviral, antiproliferative and immunomodulatory actions. Sustained virological responses were significantly greater in patients who received PEG-IFN alfa-2a versus IFN alfa-2a, with a similar side effect profile. Histological improvements were seen in patients who achieved sustained virological responses and were frequently observed among patients who did not achieve a virological response. The advantages of PEG-IFN alfa-2a were also seen in patients with cirrhosis or hepatitis C virus (HCV) genotype 1.
Clinical Pharmacology & Therapeutics | 2005
Diane R. Mould; Xiaoping Zhang; Keith Nieforth; Miklos Salgo; Neil Buss; Indravadan H. Patel
Our objective was to characterize population pharmacokinetics of enfuvirtide, 90 mg twice daily injected subcutaneously, in treatment‐experienced human immunodeficiency virus type 1 (HIV‐1)–infected patients, as well as the relationship between exposure and antiviral effect.
Clinical Transplantation | 2003
Mark D. Pescovitz; Ginny L. Bumgardner; Robert S. Gaston; Robert L. Kirkman; Susan Light; Indravadan H. Patel; Keith Nieforth; Flavio Vincenti
Abstract: Daclizumab and mycophenolate mofetil (MMF) decrease the incidence of acute allograft rejection. This double‐blind, randomized, placebo‐controlled trial was performed primarily to assess the pharmacokinetics of MMF in an immunosuppressive regimen incorporating daclizumab. At five centers, 75 renal transplant recipients were randomized 2 : 1 to receive either daclizumab 1 mg/kg or placebo pre‐transplantation and every other week, for a total of five doses. All patients received cyclosporine, steroids, and MMF. Levels of mycophenolic acid (MPA), its glucuronide metabolite, and daclizumab were measured after dosing on days 28 and 56. Safety parameters evaluated included: adverse events, laboratory abnormalities, infections, patient/graft survival, incidence of lymphoproliferative disorders, and incidence of acute rejection at 12 months. The concomitant administration of daclizumab and MMF had no effect on the pharmacokinetics of MPA: AUC0−8 values (μg h/mL ± SD) on day 28 were 30.1 ± 13.3 for daclizumab‐treat patients vs. 31.1 ± 12.4 for placebo and on day 56, 37.7 ± 18.2 for daclizumab‐treated patients vs. 35.7 ± 14.0 for placebo. Adverse events were similar between the two groups. Acute rejection at 12 months occurred in 14% of patients receiving daclizumab and 20% of patients receiving placebo. The coadministration of daclizumab did not result in a pharmacokinetic interaction with MPA, the active metabolite of MMF.
Pediatric Transplantation | 2008
Mark D. Pescovitz; Stuart J. Knechtle; Steven R. Alexander; Paul M. Colombani; Tom Nevins; Keith Nieforth; M. René Bouw
Abstract: This study examined the safety and pharmacokinetics/pharmacodynamics of daclizumab in combination with mycophenolate mofetil (or azathioprine), corticosteroids, and cyclosporine or tacrolimus, in 61 pediatric renal allograft recipients in three age groups: less than or equal to five yr (n = 18), 6–12 yr (n = 18), and 13–17 yr (n = 25). The dosing regimen was daclizumab 1.0 mg/kg before transplantation, followed by four biweekly doses. The pharmacokinetics of daclizumab were described using NONMEM software. Median (range) estimated trough daclizumab levels achieved on day 56 (before dose 5) were 3.88 μg/mL (2.48–8.78), 4.54 μg/mL (1.79–18.7), and 4.94 μg/mL (0.05–10.6) in the less than or equal to five yr (n = 15), 6–12 yr (n = 17), and 13–17 yr (n = 22) age groups, respectively. Steady‐state median (range) daclizumab exposures were 2040 mg · h/mL (1585–3778), 2757 mg · h/mL (1873–3494) and 3297 mg · h/mL (1705–6453), respectively. Saturation of the IL‐2R occurred rapidly and was maintained for greater than or equal to three months after transplantation. Daclizumab was generally well‐tolerated with no acute allergic or anaphylactic reactions, deaths or malignancies during the study. The proportion of patients who developed acute rejection at six and 12 months was 8.5% and 16.7%, respectively. This study shows that adding daclizumab at 1 mg/kg to standard immunosuppressive therapy provides safe and effective IL‐2R blockade.
Clinical Infectious Diseases | 2004
Clifford Leen; Cynthia Wat; Keith Nieforth
Enfuvirtide is the first member of the fourth class of antiretroviral drugs to become available. We present a case report of a human immunodeficiency virus (HIV)-positive patient with mild renal impairment who developed severe renal impairment secondary to tenofovir therapy while receiving enfuvirtide. Because the patients pharmacokinetic profile was not significantly altered, compared with that of HIV-infected patients with normal renal function, no dose modifications were required.
Antimicrobial Agents and Chemotherapy | 2013
B. J. Brennan; K. Wang; S. Blotner; M. O. Magnusson; J. J. Wilkins; P. Martin; J. Solsky; Keith Nieforth; Cynthia Wat; J. F. Grippo
ABSTRACT Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0–12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0–12 was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.