Pharmacokinetics and tolerability of GW420867X, a nonnucleoside reverse transcriptase inhibitor, following single escalating doses in healthy male volunteers.

The aim of the current study was to characterize the pharmacokinetics of GW420867X, a new nonnucleoside reverse transcriptase inhibitor, using a single escalating dose protocol in healthy volunteers. Four dose levels were investigated in sequential order: 300, 600, 900, and 1200 mg, with a ratio of 4:1 subjects receiving active or placebo treatment, respectively. Following single-dose administration, GW420867X was readily absorbed with a median time to peak concentration of 3 to 5 hours. GW420867X plasma exposure (AUC) was dose proportional but variable within the 300 to 1200 mg dose range. Less than dose-proportional increases were observed for Cmax. The terminal elimination t(1/2) was 50 hours, which supports once-daily dosing in future studies. Plasma trough concentrations of GW420867X at 24 hours after dosing were many fold greater than the in vitro IC50 HIV-1(HXB2) in MT4 cells. GW420867X was generally well tolerated following single-dose administration up to 900 mg; increased central nervous system-related adverse events were observed at higher doses. GW420867X had a favorable pharmacokinetic and safety profile that would enable this drug to be explored in future clinical studies with HIV-1 infected patients at doses that would provide appropriate safety and efficacy.

The bioavailability of the novel nonnucleoside reverse transcriptase inhibitor GW420867X is unaffected by food in healthy male volunteers.

The effect of food on the bioavailability of GW420867X, a novel nonnucleoside reverse transcriptase inhibitor, was investigated in 15 young, healthy, male volunteers. A single oral dose of GW420867X 100 mg was administered in the fasted state, after a high-fat meal, and after a meal of normal fat composition. Tolerability and pharmacokinetic sampling were assessed at baseline and up to 600 hours. The median concentration-time plots for each treatment group were essentially superimposable. Neither the rate nor the extent of absorption of GW420867X was significantly affected by food. The median time to peak plasma concentration was 3 to 4 hours, irrespective of treatment. Pairwise comparisons using the fasted treatment as the comparator showed no impact of food on GW420867X pharmacokinetics. GW420867X was well tolerated. There were no serious or treatment-limiting adverse events; all episodes reported were rated as mild to moderate. The bioavailability of GW420867X was unaffected by food. GW420867X may be administered independently of food and fat intake.

Pharmacokinetics and safety of escalating single and repeat oral doses of GW420867X, a novel non-nucleoside reverse transcriptase inhibitor.

OBJECTIVE: To assess the pharmacokinetics, safety and tolerability of escalating oral doses of GW420867X, a non-nucleoside reverse transcriptase inhibitor, was investigated in healthy male volunteers in a randomized, double-blind placebo-controlled study. METHODS: Study subjects were divided into four groups of 12 subjects (10, 50, 100 and 200-mg dose groups) with eight subjects from each group receiving active treatment and the remaining four matched placebo. Subjects were initially administered a single dose of GW420867X or placebo, and following a 24- to 28-day washout period, re-exposed to the same treatment for 14 consecutive days. Safety measurements including clinical laboratory evaluations, ECG and vital signs were performed before, during and after dosing. RESULTS: Geometric mean GW420867X peak plasma concentrations (Cmax) following single oral doses of 10, 50, 100 and 200 mg were 160, 608, 1,000 and 1,662 ng/ml, respectively. Time to Cmax (tmax) increased from a median value of 1 h following the 10-mg dose, to 3 h after the 200-mg dose. Geometric mean plasma areas under the curves (AUC) were 4,325 (10 mg), 17,862 (50 mg), 35,295 (100 mg) and 62,338 ng/ml per hour (200 mg) and were proportionally less than the increase in the administered dose. Apparent terminal elimination half-life (t1/2) was approximately 50 h. Following repeat dosing, accumulation ratios based on plasma AUC were: 3.0+/-1.0 (10mg), 2.6+/-0.9 (50mg), 1.8+/-0.3 (100 mg) and 1.9+/-0.8 (200 mg) after 14 days of dosing compared to the corresponding single dose. In general, oral clearance (CL/F) was greater after 14 days and greater with higher doses except for the 10-mg dose group. Steady-state CL/F was 2.2, 3.4, 4.2, and 5.1 l/h for 10, 50, 100, and 200 mg, respectively. Steady-state was generally achieved within 7-10 days. Comparison of single and repeat dosing with GW420867X showed that Cmax increased by a factor of between 1.4 to 1.8, after 14 days of daily dosing to 288 (10 mg), 1,006 (50 mg), 1,401 (100 mg) and 2,613 (200 mg) ng/ml. These increases were proportionally less than the increase in the administered dose. GW420867X was well tolerated by subjects both after single and repeated dosing. Adverse effects reported by subjects on the active drug were similar to those receiving placebo. All episodes were rated as mild to moderate in severity and resolved spontaneously without further intervention. CONCLUSION: The pharmacokinetic findings of this study imply that systemic exposure to GW420867X decreases with increasing dose and displays time-variant pharmacokinetics, which suggests decreased absorption and/or increased clearance of GW420867X. The relatively long plasma half-life, of approximately 50 h, makes it suitable for once-daily dosing.

Pulmonary function and airway responsiveness in mild to moderate asthmatics given repeated inhaled doses of zanamivir.

Zanamivir is a potent and specific inhibitor of influenza A and B virus neuraminidase, that is now approved for the treatment, and is currently under development for the prophylaxis of influenza. To assess the safety of this drug in asthmatics, 13 subjects with mild/moderate asthma [forced expiratory volume in 1 sec (FEV1)> or =70% predicted, reversibility of FEV1 to salbutamol > or =15%, concentration of methacholine causing a drop of 20% in the FEV1 (PC20FEV1)< or =8 mg ml(-1)], were recruited to a double-blind, randomized, placebo controlled, two way cross-over study. Subjects received 10 mg zanamivir as a dry powder (2 x 5 mg blisters via a Diskhaler Sovnn Plastics Ltd., Berkshire, U.K.), or a matching placebo, twice daily on day 1 and then four times daily from day 2 to day 14, in two separate periods separated by a washout period of 7 days. PC20FEV1 to methacholine was determined pre-study, on day 1 after the evening dose and on day 14 after the last dose of the study drug. FEV1 was measured pre-study and at regular intervals on days 1 and 14. Laboratory safety tests were performed on days 1, 7 and 15. Morning and evening peak expiratory flow rate (PEFR) and any adverse events were recorded in a diary card. Eleven subjects completed the study. One was withdrawn due to non-compliance, and one due to an adverse event that occurred during the placebo period. On day 1 the geometric mean PC20 for zanamivir was 36% lower than for placebo [ratio to placebo 0.64, (90% CI 0.44, 0.93)] and on day 14 this was 33% lower with zanamivir [ratio to placebo 0.67 (90% CI 0.38, 1.15)]. Both these confidence intervals were within the pre-defined interval of 'no clinically significant effect' of 0.25-4 (i.e. a change of two doubling doses of methacholine PC20FEV1 which was considered clinically significant). The time weighted mean FEV1 was 0.15 l (5.4%) lower for zanamivir on day 1 compared to placebo (90% CI 0.03, 0.28; P=0.050) and 0.01 l higher compared to placebo on day 14 (90%CI -0.12, 0.10; P=0.912). The day 1 changes were not associated with any significant symptoms or requirement for rescue bronchodilator therapy. Furthermore there was no apparent treatment difference over the 14 day dosing period in FEV1 data (90% CI: -0.11, 0.05, P=057). The mean morning PEFR was 4 l min(-1) less for zanamivir than for placebo (90% CI: -11, 3) and mean evening PEFR was 9 l min(-1) less (90% CI: -24, 5). The study treatments were well tolerated by the subjects with no clinically significant adverse events attributable to zanamivir treatment. Zanamivir inhaled as a dry powder does not significantly affect the pulmonary function and airway responsiveness of subjects with mild/moderate asthma and therefore its use in such patients subjects is not precluded.

Nasal cytokine and chemokine responses in experimental influenza A virus infection: results of a placebo-controlled trial of intravenous zanamivir treatment.

The local immune response to influenza virus infection was characterized by determining cytokine and chemokine levels in serial nasal lavage fluid samples from 15 volunteers experimentally infected with influenza A/Texas/36/91 (H1N1). The study was part of a randomized double-blind placebo-controlled trial to determine the prophylactic effect of intravenous zanamivir (600 mg 2x/day for 5 days), a highly selective inhibitor of influenza A and B virus neuraminidases, on the clinical symptoms of influenza infection. Nasal lavage fluid levels of interleukin (IL)-6, tumor necrosis factor-alpha, interferon-gamma, IL-10, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha and -1beta increased in response to influenza virus infection and correlated statistically with the magnitude and time course of the symptoms. Treatment with zanamivir prevented the infection and abrogated the local cytokine and chemokine responses. These results reveal a complex interplay of cytokines and chemokines in the development of symptoms and resolution of influenza.

Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers.

OBJECTIVE: The objective of these studies was to examine the clinical pharmacokinetics and safety of zanamivir, an influenza A and B virus neuraminidase inhibitor, when administered to healthy volunteers. DESIGN: The safety, tolerability and pharmacokinetics of zanamivir administered by a number of routes were assessed in randomised, double-blind and placebo-controlled studies. The study of absolute oral bioavailability had an open design. STUDY PARTICIPANTS: The participants in these studies were healthy male or female volunteers. INTERVENTIONS: Zanamivir was administered as single or multiple doses by the intravenous, oral, inhaled (nebuliser and dry powder) and intranasal routes. Serum and urine samples were obtained for determination of pharmacokinetic parameters, and nasal washes and throat gargles were performed to assess drug concentrations in the nose and throat. Safety was evaluated by monitoring adverse events, vital signs and laboratory parameters. RESULTS: Zanamivir was well tolerated at all doses by all routes; no serious adverse events were reported. The kinetics of zanamivir were linear with single intravenous doses up to 600 mg, and there was no evidence of modification in the kinetics after repeated twice-daily administration. Approximately 90% of zanamivir was excreted unchanged in the urine. The elimination of zanamivir from the serum was a first-order process with a half-life of approximately 2 hours and, at 16 L, the volume of distribution was similar to that of extracellular water. The absolute oral bioavailability of zanamivir was low, averaging 2%. After intranasal or oral inhaled administration, a median of 10 to 20% of the dose was systemically absorbed, with maximum serum concentrations generally reached within 1 to 2 hours. The median serum half-life ranged between 2.5 and 5.05 hours, suggesting that the elimination rate is limited by absorption. There was no evidence of modification in the kinetics after repeated inhaled administration. CONCLUSIONS: Zanamivir is a well tolerated drug. The low level of absorption of the drug after inhaled administration results in low serum concentrations, and therefore there is modest systemic exposure to zanamivir after inhalation. Zanamivir is not metabolised, and the potential for clinically relevant drug-drug interactions is very low.

Effect of renal impairment on the pharmacokinetics of intravenous zanamivir.

OBJECTIVE: Zanamivir is eliminated almost exclusively by renal excretion. This study evaluated the effect of renal impairment on the pharmacokinetics of intravenous zanamivir. DESIGN: This open-label study compared individuals with mild/moderate or severe renal impairment, as defined by creatinine clearance (CLCR), with healthy participants. STUDY PARTICIPANTS: There were 17 participants (9 men and 8 women), of whom 7 had normal renal function (CLCR > 70 ml/min), 5 had mild/moderate renal impairment (CLCR 25 to 70 ml/min) and 5 had severe renal impairment (CLCR < 25 ml/min). INTERVENTIONS: Single 4 mg doses of zanamivir were administered intravenously to healthy participants and those with mild/moderate renal impairment; participants with severe renal impairment received 2 mg. Zanamivir concentrations were determined in blood and urine. Safety was evaluated by monitoring adverse events, vital signs and laboratory parameters. RESULTS: Zanamivir was well tolerated both in participants with renal impairment and in healthy volunteers. There were no clinically significant changes attributable to zanamivir treatment. Renal dysfunction had marked effects on the pharmacokinetics of zanamivir. Although no statistically significant differences were detected between either renal impairment group and the normal renal function group for the maximum serum concentration (Cmax) or the time this occurred (tmax), a strong relationship was detected between CLCR and total body clearance (CL), renal clearance (CLR) and the terminal phase elimination rate constant (lambda z). Each 2-fold increase in CLCR produced average increases of 100, 121 and 85% in CL, CLR and lambda z, respectively. The area under the serum concentration-time curve from zero to infinity (AUC infinity) was on average increased 2-fold in individuals with mild/moderate renal impairment (4 mg dose) and 3.5-fold in those with severe impairment (2 mg dose) compared with healthy individuals (4 mg dose). CONCLUSIONS: The proposed total daily dosage of zanamivir by oral inhalation is 20 mg. Given the tolerability (observed in a separate study to be reported in this supplement) after daily intravenous dosages of 1200 mg, and the limited systemic absorption after oral inhalation, the increased drug exposure in patients with severe renal failure is not considered clinically significant. Furthermore, the local concentrations in the lung following oral inhaled delivery are essential for efficacy. Therefore, for orally inhaled zanamivir, no dosage adjustment is required in patients with renal impairment.

Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers.

OBJECTIVE: The objective of this study was to determine the sites of zanamivir deposition in the respiratory tract and the pharmacokinetics of zanamivir after oral inhalation from the Diskhaler device and from a prototype of a novel breath-activated device. DESIGN: This was a 2-period block-randomised study in which participants inhaled zanamivir from a Diskhaler and/or the prototype device on separate days. STUDY PARTICIPANTS: 13 healthy volunteers (5 men and 8 women) aged 20 to 42 years (mean age 29 years) and weighing 54.0 to 94.0 kg (mean bodyweight 69.2 kg) entered the study. INTERVENTIONS: Participants were given dry powder zanamivir 10 mg formulated with 99mTc from the Diskhaler or the prototype device on separate days. Scintigraphic images of the chest and oropharynx were recorded. Blood samples for determination of serum zanamivir and urine for excretion studies were taken up to 8 hours after drug administration. Safety was evaluated by monitoring lung function tests, adverse events and laboratory parameters. RESULTS: Orally inhaled zanamivir was well tolerated, as demonstrated by lung function tests. A mean of 13.2% (n = 11) of the 10 mg dose from the Diskhaler was deposited in the bronchi and lungs. The deposition pattern varied between individuals, showing a preferentially central deposition pattern in some and a uniform distribution pattern in others. The major deposition site was the oropharynx (mean 77.6%), with a mean of 1.2% deposited on the trachea and a mean of 3.2% retained in the blister. Similar data were obtained with the prototype device. Inhalation of zanamivir gave a broad peak of systemic absorption with mean maximum serum concentrations of approximately 30 to 40 micrograms/L after 1.5 hours. The rate and extent of absorption were similar irrespective of inhalation device. Less than 5% of drug was excreted unchanged in urine within 8 hours of inhalation, confirming the low bioavailability of zanamivir after pulmonary delivery. A significant correlation existed between systemic exposure and peripheral lung deposition. CONCLUSIONS: The local concentrations of zanamivir that result from oral inhalation via the Diskhaler are estimated to be > 10 mumol/L throughout the respiratory tract, well in excess of the concentrations observed to inhibit influenza virus neuraminidases by 50% (0.64 to 7.9 nmol/L). Similar deposition data were obtained with the Diskhaler and the prototype device, which was consequently not developed further. Pharmacoscintigraphy was confirmed as being a reliable technique for measuring zanamivir deposition in the respiratory tract.

Deposition and disposition of [11C]zanamivir following administration as an intranasal spray. Evaluation with positron emission tomography.

OBJECTIVE: This study used positron emission tomography (PET) to investigate the deposition and disposition of zanamivir administered as a nasal spray. DESIGN: This was an open-label single-dose study in healthy volunteers. STUDY PARTICIPANTS: Six healthy male volunteers, aged 19 to 33 years (mean age 25 years) with a bodyweight of 65 to 94 kg (mean bodyweight 76 kg), took part in the study. INTERVENTIONS: Each participant received by nasal spray zanamivir 6.4 mg mixed with, on average, 2.5 MBq of [11C]zanamivir. The amount of radioactivity was recorded sequentially in 5 different sectors of the body, starting with a short dynamic sequence over the nasal passage. Each of the regions was examined 1 to 4 times at different times after inhalation. The duration of the examination was 90 minutes. During this time, multiple blood samples were taken for analysis of radioactivity in whole blood. Serum samples for pharmacokinetic determinations were collected for 8 hours after administration. RESULTS: Immediately after administration, about 90% of the drug was deposited in the nasal passage, decreasing to 48% at 90 minutes after administration. Less than 2% was detected in the lower respiratory tract. The major elimination route was via the oesophagus to the stomach. Approximately 2% of the dose was absorbed; the median maximum drug concentration in serum was 15 micrograms/L, and occurred around 1.75 hours after inhalation. CONCLUSIONS: The major deposition site for zanamivir administered by nasal inhalation is the nasal passage; half of the drug remains there for at least 1.5 hours after administration. PET seems to be an excellent tool for this type of kinetic study, allowing imaging and measurements of inhaled drugs with high quantitative accuracy and good spacial resolution.

Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection.

Zanamivir is a potent inhibitor of influenza A and B virus neuraminidases and is active topically in experimental and natural human influenza. We conducted this double-blinded, placebo-controlled study to evaluate the safety and efficacy of intravenously administered zanamivir. Susceptible volunteers were randomized to receive either saline or zanamivir (600 mg) intravenously twice daily for 5 days beginning 4 h prior to intranasal inoculation with approximately 10(5) 50% tissue culture infectious doses (TCID50) of influenza A/Texas/36/91 (H1N1) virus. Reductions in the frequency of viral shedding (0% versus 100% in placebo, P < 0.005) and seroconversion (14% versus 100% in placebo, P < 0.005) and decreases in viral titer areas under the curve (0 versus 11.6 [median] log10 TCID50. day/ml in placebo, P < 0.005) were observed in the zanamivir group, as were reductions in fever (14% versus 88% in placebo, P < 0.05), upper respiratory tract illness (0% versus 100% in placebo, P < 0.005), total symptom scores (1 versus 44 [median] in placebo, P < 0.005), and nasal-discharge weight (3.9 g versus 17.5 g [median] in placebo, P < 0.005). Zanamivir was detectable in nasal lavage samples collected on days 2 and 4 (unadjusted median concentrations, 10.5 and 12.0 ng/ml of nasal wash, respectively). This study demonstrates that intravenously administered zanamivir is distributed to the respiratory mucosa and is protective against infection and illness following experimental human influenza A virus inoculation.