Xiao-Jian Zhou

Ganciclovir Treatment of Symptomatic Congenital Cytomegalovirus Infection: Results of a Phase II Study

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns in the United States. A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6 weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia (< or = 50,000/mm3) in 37 babies and absolute neutropenia (< or = 500 mm3) in 29 babies. Quantitative excretion of CMV in the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later, indicating efficacy.

Differential effects of antiretroviral nucleoside analogs on mitochondrial function in HepG2 cells

ABSTRACT Numerous studies have reported effects of antiviral nucleoside analogs on mitochondrial function, but they have not correlated well with the observed toxic side effects. By comparing the effects of the five Food and Drug Administration-approved anti-human immunodeficiency virus nucleoside analogs, zidovudine (3′-azido-3′-deoxythymidine) (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxyinosine (ddI), 2′,3′-didehydro-2′,3′-deoxythymidine (d4T), and β-L-2′,3′-dideoxy-3′-thiacytidine (3TC), as well as the metabolite of AZT, 3′-amino-3′-deoxythymidine (AMT), on mitochondrial function in a human hepatoma cell line, this issue has been reexamined. Evidence for a number of mitochondrial defects with AZT, ddC, and ddI was found, but only AZT induced a marked rise in lactic acid levels. Only in mitochondria isolated from AZT (50 μM)-treated cells was significant inhibition of cytochrome c oxidase and citrate synthase found. Our investigations also demonstrated that AZT, d4T, and 3TC did not affect the synthesis of the 11 polypeptides encoded by mitochondrial DNA, while ddC caused 70% reduction of total polypeptide content and ddI reduced by 43% the total content of 8 polypeptides (including NADH dehydrogenase subunits 1, 2, 4, and 5, cytochromec oxidase subunits I to III, and cytochrome b). We hypothesize that in hepatocytes the reserve capacity for mitochondrial respiration is such that inhibition of respiratory enzymes is unlikely to become critical. In contrast, the combined inhibition of the citric acid cycle and electron transport greatly enhances the dependence of the cell on glycolysis and may explain why apparent mitochondrial dysfunction is more prevalent with AZT treatment.

Simultaneous quantitation of the 5′-triphosphate metabolites of zidovudine, lamivudine, and stavudine in peripheral mononuclear blood cells of HIV infected patients by high-performance liquid chromatography tandem mass spectrometry

A high-performance liquid chromatography (HPLC) method utilizing triple quadrupole mass spectrometry (MS) detection was developed and validated for the simultaneous measurement of the intracellular nucleoside 5′-triphosphate anabolites of zidovudine (ZDV-TP), lamivudine (3TC-TP), and stavudine (d4T-TP). These compounds were extracted from patient peripheral blood mononuclear cells (PBMCs) which are the sites of HIV replication and drug action. Ion-exchange solid phase extraction (SPE) followed by enzymatic digestion with alkaline phosphatase was utilized to yield the measurable nucleoside forms of the nucleotides. Reversed phase C-18 SPE with addition of a nucleoside internal standard, 3′-azido-2′,3′-dideoxyuridine (AzdU) allowed for the indirect measurement of the original 5′-triphosphate concentration by HPLC/MS/MS. Quantitation was performed from calibration curves generated from authentic 5′-triphosphate standards spiked in PBMCs from healthy volunteers. Analytical range for the three 5′-triphosphates was equivalent to 50–45,000 pg. Mean interassay accuracies for 3TC-TP, d4T-TP, and ZDV-TP (n > 90) were 99.4%, 100.1%, and 108.0%, respectively. Mean interassay precisions (%C.V.) for 3TC-TP, d4T-TP, and ZDV-TP (n > 90) were 8.8%, 10.4%, and 8.2%, respectively. Recovery of the extraction method was 79.2%, 83.1%, and 98.3% for 3TC-TP, d4T-TP, and ZDV-TP, respectively. This method can be utilized to measure the intracellular 5′-triphosphate levels in HIV infected patients receiving antiretroviral therapy containing the nucleoside reverse transcriptase inhibitors 3TC, d4T, or ZDV.

Safety and Pharmacokinetics of IDX184, a Liver-Targeted Nucleotide Polymerase Inhibitor of Hepatitis C Virus, in Healthy Subjects

ABSTRACT IDX184 is a nucleotide prodrug designed to enhance formation in the liver of the active triphosphate of 2′-methylguanosine (2′-MeG), a potent and specific polymerase inhibitor of the hepatitis C virus (HCV). In the present study, single ascending oral doses of 5, 10, 25, 50, 75, and 100 mg IDX184 were administered sequentially to cohorts of 8 healthy subjects, randomized 6:2, active/placebo. Plasma and urine pharmacokinetic sampling was performed over a period of 120 h after dosing. Upon absorption, IDX184 rapidly disappeared from plasma, with a mean half-life (t 1/2) of approximately 1 h, while plasma concentrations of 2′-MeG gradually increased. Consistent with a liver-targeting approach, plasma exposure of IDX184 and 2′-MeG was low and was also dose related: the mean maximum concentrations ranged from 1.1 to 17 ng/ml for IDX184 and 1.7 to 19 ng/ml for 2′-MeG, and the respective mean total area under the curve ranged from 1.2 to 22.7 and 17.3 to 334 ng·h/ml. Mean 2′-MeG plasma concentrations 24 h after dosing were 0.6 to 3 ng/ml for the 25- to 100-mg doses. Mean 2′-MeG t 1/2 values ranged from 18 to 43 h for doses of 25 mg and above. Mean cumulative urine excretion was 0.2% and 12 to 20% of administered doses for the unchanged IDX184 and 2′-MeG, respectively. IDX184 was safe and well tolerated; no serious adverse events (SAEs), dose-dependent adverse events (AEs), or dose-limiting toxicities were observed. The incidence of AEs and laboratory abnormalities was low and was similar among subjects receiving IDX184 or a placebo. All AEs were mild to moderate and resolved at the end of study. The favorable safety and pharmacokinetic profiles support further clinical evaluation of IDX184 in HCV-infected patients.

Pharmacokinetics of Telbivudine in Healthy Subjects and Absence of Drug Interaction with Lamivudine or Adefovir Dipivoxil

ABSTRACT Two phase I studies were conducted to assess the plasma pharmacokinetics of telbivudine and potential drug-drug interactions between telbivudine (200 or 600 mg/day) and lamivudine (100 mg/day) or adefovir dipivoxil (10 mg/day) in healthy subjects. Study drugs were administered orally. The pharmacokinetics of telbivudine were characterized by rapid absorption with biphasic disposition. The maximum concentrations in plasma (Cmax) were reached at median times ranging from 2.5 to 3.0 h after dosing. Mean single-dose Cmax and area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) were 1.1 and 2.9 μg/ml and 7.4 and 21.8 μg · h/ml for the 200- and 600-mg telbivudine doses, respectively. Steady state was reached after daily dosing for 5 to 7 days. The mean steady-state Cmax and area under the plasma concentration-time curve over the dosing interval (AUCτ) were 1.2 and 3.4 μg/ml and 8.9 and 27.5 μg · h/ml for the 200- and 600-mg telbivudine repeat doses, respectively. The steady-state AUCτ of telbivudine was 23 to 57% higher than the single-dose values. Concomitant lamivudine or adefovir dipivoxil did not appear to significantly alter the steady-state plasma pharmacokinetics of telbivudine; the geometric mean ratios and associated 90% confidence interval (CI) for the AUCτ of telbivudine alone versus in combination were 106.3% (92.0 to 122.8%) and 98.6% (86.4 to 112.5%) when coadministered with lamivudine and adefovir dipivoxil, respectively. Similarly, the steady-state plasma pharmacokinetics of lamivudine or adefovir were not markedly affected by the coadministration of telbivudine; the geometric mean ratios and associated 90% CI, alone versus in combination with telbivudine, were 99.0% (87.1 to 112.4%) and 92.2% (84.0 to 101.1%), respectively, for the lamivudine and adefovir AUCτ values. Moreover, the combination regimens studied were well tolerated in all subjects. The results from these studies provide pharmacologic support for combination therapy or therapy switching involving telbivudine, lamivudine, and adefovir dipivoxil for the treatment of chronic hepatitis B virus infection.

Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection : Pharmacodynamic implications

ABSTRACT The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times Tmax to the maximum plasma concentration (Cmax) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum Cmaxs and the areas under the plasma concentration-time curve from time zero to time t (AUC0-ts) increased proportionally with dose. At steady-state, the values of Cmax and AUC0-t were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for Cmax and from 1.40 to 1.70 for AUC0-t. While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state Cmax and AUC0-t. In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.

Single-Dose Escalation and Multiple-Dose Safety, Tolerability, and Pharmacokinetics of IDX899, a Candidate Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Subjects

ABSTRACT IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50- to 400-mg doses) and then fed (≥200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (t1/2) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean t1/2 of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 μg/ml (range, 0.2 to 2.5 μg/ml) and 2.1 μg/ml (range, 0.5 to 4.5 μg/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.

Absence of Food Effect on the Pharmacokinetics of Telbivudine Following Oral Administration in Healthy Subjects

The influence of food on the pharmacokinetics of telbivudine, a candidate antiviral agent against hepatitis B virus (HBV), was investigated in healthy adult subjects following a 600‐mg oral dose administered with and without a high‐fat/high‐calorie meal. Telbivudine was well tolerated under fasting and fed conditions. Oral absorption of telbivudine as measured by maximum plasma concentration (Cmax), time to reach Cmax (Tmax), and area under the plasma concentration‐time curve (AUC0‐t and AUC0‐∞) was not altered by food intake immediately before oral dosing. Values of Cmax, Tmax, and AUC were comparable when telbivudine was administered under fed and fasting conditions. Results from this study indicated that the absorption of telbivudine was not affected by a high‐fat/high‐calorie meal; telbivudine can therefore be administered orally with no regard to the timing of meals.

Single-dose and multiple-dose pharmacokinetics and safety of telbivudine after oral administration in healthy chinese subjects

The pharmacokinetics of telbivudine, an L‐nucleoside with potent activity against hepatitis B virus, was assessed in 42 healthy Chinese volunteers. Subjects were assigned to receive a single oral dose of 200, 400, or 800 mg telbivudine or repeat doses of 600 mg/d. Telbivudine was absorbed rapidly and exhibited dose‐related plasma exposure. After reaching maximum concentration (Cmax) at a median time of 2.0 to 2.5 hours, plasma disposition of the drug was biphasic with a mean terminal half‐life ranging from 39.4 to 49.1 hours. Telbivudine accumulated slightly after repeat doses, and steady state was reached after 5 to 6 consecutive doses of 600 mg/d. The mean steady‐state Cmax and area under the plasma concentration–time curve over the dosing interval of telbivudine 600 mg were 3.7 μg/mL and 26.1 μg·h/mL, respectively. Cumulative urinary excretion of telbivudine over 32 hours represented 24.4% of the administered dose, with a mean renal clearance of 6.6 L/h. Telbivudine was well tolerated in the studied dose range in healthy Chinese subjects, with no pattern of dose‐related clinical or laboratory adverse events.

A randomized, double-blind, multiple-dose study of the pan-genotypic NS5A inhibitor samatasvir in patients infected with hepatitis C virus genotype 1, 2, 3 or 4

BACKGROUND & AIMS Samatasvir is a pan-genotypic inhibitor of the hepatitis C (HCV) non-structural protein 5A (NS5A). This study evaluated the antiviral activity, pharmacokinetics and safety of samatasvir monotherapy in treatment-naïve subjects infected with HCV genotype 1-4. METHODS Thirty-four genotype 1 and thirty genotype 2, 3 or 4 subjects were randomized to receive for 3days placebo or samatasvir 25-100mg per day. Plasma samples for HCV RNA, pharmacokinetics and sequencing were collected up to day 10. RESULTS Samatasvir achieved potent antiviral activity across genotypes: mean maximum reductions from baseline were 3.2-3.6 (genotype 1a), 3.0-4.3 (genotype 1b), 3.2-3.4 (genotype 3), and 3.6-3.9 (genotype 4) log10/ml respectively; no viral rebound was observed during the 3-day treatment period. For genotype 2 HCV, samatasvir was active in subjects with NS5A L31 polymorphism at baseline (individual range 2.5-4.1 log10/ml), but showed minimal activity in those with baseline M31 polymorphism. Samatasvir exhibited a long plasma half-life of approximately 20h which supports once daily dosing. Samatasvir was well tolerated in all subjects with no safety-related discontinuations or serious adverse events. The most common adverse events included constipation, nausea and headache and occurred at similar frequency in active and placebo subjects. All events were mild or moderate in intensity. There were no patterns or dose dependence of adverse events, vital signs, laboratory parameters or electrocardiograms. CONCLUSIONS Samatasvir 25-100mg monotherapy for 3days was well tolerated and induced a rapid and profound reduction in plasma HCV RNA in subjects infected with HCV genotype 1-4. Samatasvir is being evaluated in combination with other direct-acting antiviral agents in subjects with HCV infection.