Cost-utility analysis of antiviral use under pandemic influenza using a novel approach - linking pharmacology, epidemiology and heath economics.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) - dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients' quality of life. Integrating PK/PD-EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

Safety, tolerability, and pharmacokinetics of ribavirin in hepatitis C virus-infected patients with various degrees of renal impairment.

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.

Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects.

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.

Substituted thiadiazolines as inhibitors of central nervous system carbonic anhydrase.

A series (24-30) of substituted thiadiazolines was synthesized and tested for in vitro carbonic anhydrase inhibition and for protective ability against pentylenetetrazole-induced convulsions. ED50 (pentylenetetrazole protection), TD50, and LD50 values are reported for each compound. With the exception of 30, all compounds approximated the model compound methazolamide as in vitro carbonic anhydrase inhibitors. Several of the compounds produced extended protection against pentylenetetrazole-induced convulsions. Ring methoxy substitution in the ortho position appeared to produce maximum activity.

Synthesis and biological activity of cocaine analogues. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones.

1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.

A phase I trial of humanized anti-interleukin 2 receptor antibody in renal transplantation.

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.

Peginterferon alfa-2a (40 kDa) monotherapy: a novel agent for chronic hepatitis C therapy.

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 EC(50) 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.

The pharmacokinetics and tolerability of the oral neuraminidase inhibitor oseltamivir (Ro 64-0796/GS4104) in healthy adult and elderly volunteers.

The tolerability and pharmacokinetics of Ro 64-0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double-blind, placebo-controlled studies. Two studies involved healthy adult volunteers (18-55 years) (n = 48) who received single (20-1000 mg) or bid doses (50-500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (> or = 65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple-dose exposure was predictable from single-dose data, and steady-state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice-daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.

Retrospective study of drug response in 87 patients with progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease that responds poorly to pharmacologic intervention despite its clinical, neurochemical, and pathologic similarity to Parkinson's disease. We reviewed our experience with drugs used in the treatment of patients with PSP who were followed in the Department of Neurology, University of Medicine and Dentistry of New Jersey--Robert Wood Johnson Medical School. Of 136 patients identified, adequate drug-response data were available for 87 (64%). Benefit and adverse effects of therapy were graded on a 4-point scale: 0, none; 1, minimal; 2, moderate; 3, marked. The three most frequently used drugs were amitriptyline (32% of patients benefited), imipramine (28% of patients benefited) and levodopa/carbidopa (Sinemet) (38% of patients benefited). Levodopa/carbidopa, amantadine, selegiline, and amitriptyline gave the best risk/benefit ratios. Monotherapy tended to show more benefit and fewer adverse effects than polypharmacy.

Synthesis of potential mescaline antagonists.

1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

Synthesis and biological activity of cocaine analogs I: N-alkylated norcocaine derivatives.

N-Allylnorcocaine, N-dimethylallylnorcocaine, and N-cyclopropylmethylnorcocaine were prepared and examined for cocaine-like activity. The compounds were prepared by alkylation of norcocaine, which was obtained by demethylation of cocaine with 2,2,2-trichloroethyl chloroformate followed by zinc--acetic acid reduction. The compounds were evaluated by comparison with cocaine in causing disruption of milk intake in rats, behavioral modification in squirrel monkeys, and inhibition of 3H-serotonin uptake by rat synaptosomes. The compounds showed cocaine-like activity less potent than cocaine in the latter two tests and were inactive in the milk intake test.