Cost-effectiveness analysis of tenofovir disoproxil fumarate for treatment of chronic hepatitis B in China.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is newly available for treatment of chronic hepatitis B patients in China. To date, no study has been conducted to examine the cost-effectiveness of this treatment. The aim of this study was to estimate the cost-effectiveness of TDF versus four oral nucleos(t)ide analogs [lamivudine (LAM), adefovir (ADV), telbivudine (LdT), and entecavir (ETV)] and from a pharmacoeconomic perspective to assess current drug pricing for TDF. METHODS: Based on Chinese healthcare perspectives, a Markov model was applied to simulate the lifetime (40-year time span) costs and quality-adjusted life-years (QALYs) for five different monotherapy strategies. Two kinds of rescue combination strategies (base-case: LAM + ADV then ETV + ADV; alternative: directly using ETV + ADV) were separately considered for treatment of patients refractory to monotherapy. Model parameters (including disease transition, cost, and utility) were obtained from previous Chinese population studies. Both branded and generic drugs were separately analyzed. Study model uncertainties were assessed by one-way and probabilistic sensitivity analyses. Two-way sensitivity analysis was used to explore uncertainties between efficacy and price of TDF. RESULTS: In the base-case analysis, the lowest lifetime cost and the best cost-effectiveness ratio were obtained by ETV, which was considered the reference treatment. LAM, ADV, and LdT treatments had significantly greater costs and lower efficacies. Compared to ETV, TDF was more effective but also more expensive. The incremental cost-effectiveness ratios of TDF versus ETV were much higher than the willing-to-pay threshold of $20,466 US dollars (USD) per QALY gained (3 × gross domestic product per capita of China, 2014). TDF would be the most cost-effective strategy if the annual cost did not exceed $2260 USD and $1600 USD for branded and generic drugs, respectively. CONCLUSIONS: For Chinese chronic hepatitis B patients, ETV is still the most cost-effective strategy over TDF and other nucleos(t)ide analogs, with a threshold of $20,466 USD/QALY gained.

Maternal dietary uridine causes, and deoxyuridine prevents, neural tube closure defects in a mouse model of folate-responsive neural tube defects.

BACKGROUND: Folic acid prevents neural tube closure defects (NTDs), but the causal metabolic pathways have not been established. Serine hydroxymethyltransferase 1 (SHMT1) is an essential scaffold protein in folate-dependent de novo thymidylate synthesis in the nucleus. SHMT1-deficient mice provide a model to investigate folic acid-responsive NTDs wherein disruption of de novo thymidylate synthesis impairs neural tube closure. OBJECTIVE: We examined the effects of maternal supplementation with the pyrimidine nucleosides uridine, thymidine, or deoxyuridine with and without folate deficiency on NTD incidence in the Shmt1 mouse model. DESIGN: Shmt1(+/+) and Shmt1(-/-) female mice fed folate-replete or folate-deficient diets and supplemented with uridine, thymidine, or deoxyuridine were bred, and litters (n = 10-23 per group) were examined for the presence of NTDs. Biomarkers of impaired folate status and metabolism were measured, including plasma nucleosides, hepatic uracil content, maternal plasma folate concentrations, and incorporation of nucleoside precursors into DNA. RESULTS: Shmt1(+/-) and Shmt1(-/-) embryos from dams fed the folate-deficient diet were susceptible to NTDs. No NTDs were observed in litters from dams fed the folate-deficient diet supplemented with deoxyuridine. Surprisingly, uridine supplementation increased NTD incidence, independent of embryo genotype and dietary folic acid. These dietary nucleosides did not affect maternal hepatic uracil accumulation in DNA but did affect plasma folate concentrations. CONCLUSIONS: Maternal deoxyuridine supplementation prevented NTDs in dams fed the folate-deficient diet, whereas maternal uridine supplementation increased NTD incidence, independent of folate and embryo genotype. These findings provide new insights into the metabolic impairments and mechanisms of folate-responsive NTDs resulting from decreased Shmt1 expression.

Nonclinical Safety Profile of BMS-986001, a Nucleoside Transcriptase Inhibitor for Combination Retroviral Therapy.

Nucleoside reverse transcriptase inhibitors (NRTIs)/nucleotide reverse transcriptase inhibitors are key components of combination antiretroviral therapy for HIV infection. First-generation NRTIs are associated with mitochondrial toxicity in patients, mainly due to inhibition of human DNA polymerase γ (hDNA polγ) that manifests as adverse events such as lipodystrophy, lactic acidosis, myopathy, cardiomyopathy, or nephropathy in patients. In chronic nonclinical studies in rodents and nonrodents, eukaryotic (host) mitochondrial toxicity manifests as some drug-specific toxicities similar to human toxicity. BMS-986001, a novel thymidine analog with minimal hDNA polγ inhibition, has demonstrated antiretroviral activity in early clinical studies. The primary toxicity of BMS-986001 in rats and monkeys is bone marrow dyserythropoiesis with associated decreases in red blood cell mass. Additionally, at high doses, severe platelet reductions accompanied by cutaneous petechiae began during weeks 8 and 11 in 3 of 60 monkeys in chronic toxicity studies. In a 6-month study, platelet reductions required euthanasia of the 2 affected monkeys (300 mg/kg/d) at week 14, but with dose reduction (200 mg/kg/d) remaining monkeys had no platelet changes. One affected monkey (200 mg/kg/d) in a 9-month study completed dosing and its platelet counts recovered during a 1-month recovery. Formation of platelet-bound immunoglobulin in the presence of BMS-986001, together with rapid and complete platelet recovery in the absence of BMS-986001, suggested that platelet decreases in monkeys may be immune mediated. No findings indicative of mitochondrial toxicity were observed in rats or monkeys given BMS-986001, suggesting an improved safety profile compared to marketed NRTI or tenofovir disoproxil fumarate.

Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome.

PURPOSE: To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity. METHODS: Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death. RESULTS: Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity. CONCLUSION: Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.

Oat lipids-induced covalent DNA modifications (I-compounds) in female Sprague-Dawley rats, as determined by 32P-postlabeling.

Previous studies have shown that the presence of oats in the diet contributes to formation of I-compounds (age-dependent covalent DNA modifications detected by 32P-postlabeling assay) in female Sprague-Dawley rat liver DNA. The current study explored the possible ingredients in oats responsible for the observed effects on DNA. Feeding AIN-76A diet containing 5% oat lipids (obtained by methanol extraction and dissolved in trioctanoin) in place of corn oil for 2 months successfully induced the formation of 3 oats-specific (spots 2-4) and 4 natural ingredient diet-specific I-compounds (spots 6-9) in liver DNA. Barley, an oatlike cereal, induced 3 of these spots at very low intensities but not the 3 oats-specific I-spots. Oral administration of oat lipids to weanling rats of both sexes for 7 days elicited trace amounts of the oats-specific spots and spot 9 in liver DNA. However, when oat lipids were given at 6 or 9 weeks of age, the oats-specific spots were detected at high levels in female but not in male rats. These oats-related DNA modifications were also present in 6-week-old female rats which had received oat lipids p.o. for 2 or 3 days or i.p. for 4 days. Rats given trioctanoin or extracts from natural ingredient Wayne diet (lacking oats) did not show any of these spots. On the other hand, rats treated with extracts from an oats-containing Teklad diet displayed a trace amount of one of these I-compounds. Oat lipids did not induce any extra spots in rat kidney DNA. Feeding of AIN diet supplemented with oats to female Syrian hamsters did not elicit any renal or hepatic DNA alterations, as detected by 32P-postlabeling. Rats fed oat lipids-supplemented AIN diet or Purina diet showed the highest levels of I-compounds overall in liver among all dietary groups and these two groups also had significantly higher hepatic DNA synthesis rates. Oat lipids enhanced kidney DNA synthesis also. The total hepatic or renal cytochrome P-450 contents were not significantly affected by different diets. These results demonstrate a novel link between a natural dietary ingredient and covalent DNA modifications and shed light on the origins of certain I-compounds.

Schedule-dependent antitumor and toxic effects of thymidine and 5-fluorouracil in AKR and L1210 leukemias.

The effect of thymidine (dThd) on 5-fluorouracil (FUra) toxicity to both leukemia stem cells (LCFU) and hematopoietic stem cells (NCFU) was examined. A dose of 10 mg/mouse of dThd given within 1 h before FUra enhanced FUra cytotoxicity to NCFU by a factor of about 4. This effect was also reflected in the reduction of the LD10. The dose-survival curve of FUra in AKR leukemia was modified by the prior administration of dThd 10 mg/mouse: the cytotoxic effect of FUra was enhanced by a factor of between 100 and 1000 throughout the dose range studied. These findings were reflected in the ILS studies. When given by 'high dose' infusion dThd had only a slight antitumor effect on AKR leukemia, and no effect on L1210. When large doses of dThd were infused concomitantly with FUra they potentiated its cytotoxicity against NCFU, AKR LCFU, and L1210 LCFU in a dose-dependent manner and by a maximum factor of about 70.

A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma.

Three hundred thirty-five previously untreated patients with advanced colorectal carcinoma were randomly assigned to treatment with 5-fluorouracil (5-FU) alone, 5-FU plus N-(phosphonacetyl)-L-aspartic acid (PALA), 5-FU plus high-dose thymidine, 5-FU plus levamisole, or 5-FU plus methyl CCNU, vincristine, and streptozotocin (MOF-Strept). Dosages were designed to produce definite toxicity in the majority of patients, although the nature of dose-limiting reactions varied considerably among regimens. 5-FU alone and 5-FU plus levamisole produced mucocutaneous reactions, diarrhea, and leukopenia; 5-FU plus PALA produced primarily mucocutaneous reactions and diarrhea; 5-FU plus thymidine produced leukopenia with occasional neurotoxicity and hypotension; and MOF-Strept produced substantial nausea and vomiting with both thrombocytopenia and leukopenia. Objective response rates among patients with measurable disease varied from 12% (5-FU plus PALA) to 34% (MOF-Strept), but none of the regimens were significantly superior to 5-FU alone. Both interval to progression and survival were comparable among the five regimens with no reasonable chance that any combination regimen could produce as much as a 50% improvement when compared with 5-FU alone. Whereas we observed definite modulation of 5-FU dose--toxicity relationships, particularly with the thymidine and PALA combinations, this did not result in a detectable improvement in therapeutic effect. None of the combination regimens, administered in the dosages and schedules we used, can be recommended as standard therapy of advanced colorectal carcinoma.

Plasma kinetics and effects of 5,6-dihydro-5-azacytidine in mice and L1210 tumor.

The plasma kinetics of 5,6-dihydro-5-azacytidine (DHAC) was determined in mice using an HPLC method following an intravenous dose of 2000 mg/kg (LD10). Pharmacokinetic parameters calculated from these single dose data were sufficient to predict steady state plasma concentrations produced by s.c. infusion of DHAC. Lethal toxicity (LD66) occurred at an infusion rate of 37 mg/kg/h (111mg/m2/h), corresponding to a plasma steady-state DHAC concentration 38 +/- 14 micrograms/ml when the infusion time was 96 h; no lethality occurred at infusion times of 72 h or less. In vitro clonogenic assays and in vivo therapeutic experiments with L1210 tumor indicated that increasing the exposure time at concentrations near 25 micrograms/ml from 24 to 72 h increased the cell kill only slightly. The maximum log cell kill of L1210 estimated from either in vitro or in vivo data was 1.5 logs.

Thymine arabinoside (Ara-T) topical and iontophoretic application for herpes simplex virus type 1 and type 2 skin infections in hairless mice.

The antiviral agent thymine arabinoside (9-beta-D-arabinofuranosyl thymine, Ara-T) was applied topically and by anodal (+) iontophoresis in a NaCl solution to Herpes simplex virus type 1 (HSV-1), and Herpes simplex virus type 2 (HSV-2) skin infections in hairless mice. The chemotherapeutic efficacy of Ara-T was evaluated employing the parameters of mean lesion score, number of mice with signs of neurological involvement (paralysis), mortality and mean survival time. Anodal (+) iontophoresis of 0.4% Ara-T in a 0.1 M NaCl solution significantly suppressed HSV-1 skin infection, but the infection was not altered by topical application of 3% Ara-T. HSV-2 infection was refractory to both topical and iontophoretic application of Ara-T. This is the first report of the in vivo efficacy of Ara-T for HSV-1 skin infections.

Methotrexate-induced renal impairment: clinical studies and rescue from systemic toxicity with high-dose leucovorin and thymidine.

Four separate groups of patients have been studied: (1) The effect of high-dose methotrexate (MTX) administration on glomerular filtration rate was determined by pre- and posttreatment inulin and creatinine clearances in nine patients. Measurements were made prior to and 24-40 hr after drug administration. Inulin and creatinine clearances both decreased a mean of 43%. No signs of systemic toxicity occurred. (2) Three other patients given high-dose courses of MTX developed MTX toxicity. Their creatinine clearance decreased an average of 61%. (3) In a separate group of five patients undergoing weekly MTX treatment, comparison of serum MTX pharmacokinetics with and without alkalinization of the urine demonstrated no significant difference in peak serum MTX levels or serum MTX decay. (4) Eight additional patients with severe renal dysfunction secondary to MTX were treated with increased doses of leucovorin and a continuous infusion of thymidine (8 g/m2/day) once renal failure was recognized. When high-dose leucovorin and thymidine were begun 48-72 hr after the MTX infusion, severe toxicity in the form of leukopenia, thrombocytopenia, diffuse mucositis, stomatitis, or skin rash was averted. We concluded the following: (1) high-dose MTX causes a subclinical decrease in glomerular filtration rate with each administration, even in nontoxic courses; (2) alkalinization of the urine with sodium bicarbonate does not alter plasma MTX decay, while volume expansion (hydration) is maintained constant; and (3) rigorous monitoring of serum creatinine and serum MTX levels 24-48 hr after MTX administration allows for the institution of rescue measures, including leucovorin and thymidine, which will abort the systemic toxicity that accompanies MTX-induced renal failure.

Comparison of pharmacokinetics of 5-fluorouracil and 5-fluorouracil with concurrent thymidine infusions in a Phase I trial.

The serum half-life of 5-fluorouracil (5-FUra) in humans is best described as a biexponential decay function, with t1/2 alpha = 7.8 +/- 2.6 (S.E.) min and t1/2 beta = 36.8 +/- 13.5 min during initial courses of this drug alone. Pharmacokinetics of 5-FUra during courses of daily therapy (for 5 days) revealed prolongation of t1/2 in both components of the decay curve, which has not been previously reported. Despite the efficacy of thymidine (dThd) given as a continous i.v. infusion of 8 g/sq m/day in prevention of high-dose methotrexate toxicity, continuous infusion of dThd at this dose does not prevent the toxicity of 5-FUra orreverse inhibition of DNA and RNA synthesis by 5-fura. On the contrary, continuous infusion of dThd appears to increase the toxicity of 5-FUra during continuous dThd infusion revealed prolongation of the 5-FUra t1/2 which remained stable through the course of 5 days of 5-FUra with dThd. This protracted t1/2 is believed to account at least in part for the increased toxicity of 5-FUra with dThd. Dose-limiting mucositis, myelosuppression, and gastrointestinal toxicity were observed at 5-FUra doses ranging from one-half to two-thirds the customarily tolerated dose of 5-FUra alone in similar courses of daily bolus therapy (for 5 days).

The detection of various nitrosamines in the hepatocyte primary culture/DNA repair test.

Evaluation of 6 carcinogenic nitrosamines in the hepatocyte primary culture/DNA repair test revealed that all were active. Three non-carcinogenic analogs were negative. This sensitivity to nitrosamines, together with considerations concerning the metabolic capability and end point of this assay, indicates that it will be a useful addition to screening batteries that include bacterial mutagenesis assays.

In vivo enhancement of 5-fluorouracil cytotoxicity to AKR leukemia cells by thymidine in mice.

The spleen colony assay was used to examine the effect of thymidine (dThd) on 5-fluorouracil (FUra) cytotoxicity in two transplantable leukemias, AKR (in AKR mice) and L1210 [in (BALB/c x DBA/2)F1 mice], in vivo. A large dose of dThd (10 mg/mouse) could not rescue these cell lines from FUra toxicity. Instead, when dThd was given within 1 hour before FUra, it enhanced FUra cytotoxicity by a factor between 100 and 1,000 in AKR leukemia. That dThd increased the cytotoxicity of FUra only by a factor of 3 in L1210 leukemia suggested a different mechanism of interaction of the two drugs in the two cell lines. Examination in hybrid mice capable of supporting the growth of both leukemias showed the enhancement to be tumor related rather than host related. We also demonstrated a dose-dependent effect of dThd injection 15 minutes before FUra in AKR leukemia. Concerning the kinetics of killing of AKR leukemia colony-forming units (LCFU) following the administration of dThd 15 minutes before FUra, LCFU survival continued to decrease for 24--36 hours following drug administration.

Modulation versus rescue of antimetabolite toxicity by salvage metabolites administered by continuous infusion.

A system has been developed for the long-term continuous intravenous infusion of chemotherapeutic agents into unrestrained mice which allows new approaches to the toxicological and chemotherapeutic evaluation of antimetabolites. In mice, the concurrent infusion of thymidine and a source of preformed purine reversed both the toxicity and antitumor activity of MTX comparable to what was previously observed in cell culture. The infusion of thymidine alone, however, also blocked the toxicity of MTX without interfering with antitumor activity. A comparison of leucovorin rescue versus the utilization of thymidine plus preformed purine indicated that these salvage metabolites were as effective as leucovorin in reducing the toxicity of high-dose MTX while retaining antitumor activity.

Mode of action of chemotherapy in vivo on human acute leukemia. I. Daunomycin.

The leukocytes of 16 adult patients with acute myeloblastic leukemia were studied by autoradiographic methods to elucidate the mode of action of daunomycin. It was shown that daunomycin, at clinically useful doses, exhibits a cytolytic effect on all leukemic blasts whatever their cell-cycle phase. This cytolytic action affects, however, preferentially S-phase cells. It was shown also that blasts of patients less sensitive to daunomycin or receiving a lesser dose of the drug are temporarily blocked in G(2) phase (delayed mitosis) or in G(2) phase (prolonged generation time). Finally daunomycin appeared to hamper the passage of G(2)-blocked blasts from the bone marrow to the blood, while G(2)-phase cells crossed freely.