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Antimicrobial Agents and Chemotherapy, April 1998, p. 903-906, Vol. 42, No. 4
C.H.U. Saint-Pierre, Brussels,
Belgium,1 and
Zeneca Pharmaceuticals,
Macclesfield, England2
Received 21 April 1997/Returned for modification 15 June
1997/Accepted 23 December 1997
D0870 is a triazole with a broad antifungal spectrum, and it has
been shown to have both in vitro and in vivo activities against wild-type and fluconazole-resistant strains of Candida
albicans. Twenty-two human immunodeficiency virus (HIV)-positive
male subjects were enrolled in an open, nonrandomized trial
investigating the pharmacokinetics of two different dosing regimens of
D0870 and assessing the safety of multiple oral doses of D0870 in
HIV-positive subjects and their ability to tolerate multiple oral
doses. Nine subjects received an initial loading dose of 50 mg,
followed by four once-daily maintenance doses of 10 mg. A further nine
subjects received an initial 200-mg loading dose followed by four daily maintenance doses of 25 mg. All subjects were fasting. A single loading
dose of 50 mg of D0870 resulted in a mean maximum concentration in
serum (Cmax) of 107 ± 32 ng/ml.
Concentrations in plasma were maintained by the 10-mg once-daily dosing
regimen as seen by the similar values of the area under the
concentration-time curve from 0 to 24 h following dosing on days 1 and 5 and a mean accumulation ratio close to unity (0.90). The terminal
plasma half-life of D0870 in plasma following dosing on day 5 ranged from 23 to 85 h (mean, 49 h). A single loading dose of
200 mg of D0870 resulted in a Cmax of 431 ± 186 ng/ml. Concentrations in plasma were again maintained by the
25-mg daily dosing regimen, with the mean accumulation ratio being close to unity (1.17). The terminal half-life of D0870 in plasma following dosing on day 5 of phase II of the study
ranged from 34 to 137 h (mean, 71 h). In addition, the
concentrations achieved in the plasma of these HIV-positive subjects
were similar to the values predicted from simulations based on data
derived from normal, healthy subjects. D0870 was well tolerated. No
serious adverse events were experienced during the course of the study, and all volunteers completed the trial. A total of 15 adverse events
were reported, but none were considered to be related to the
administration of D0870 and all had resolved by the end of the trial.
No changes in the hematology, clinical chemistry, or urinalysis
parameters were considered to be related to dosing with D0870.
No clinically significant changes in the electrocardiogram parameters
were noted during the trial. The data generated in this trial support
further investigation of these regimens with HIV-positive subjects
with fluconazole-susceptible or -resistant oropharyngeal candidosis.
D0870 is a bistriazole antifungal
agent which is highly active in vitro against a wide range of fungi. In
particular, it has potent activity against wild-type and
fluconazole-resistant strains of Candida albicans. It is
effective in the treatment of a range of experimental infections in
both normal and immunocompromised animals (1, 4-6, 8-11, 13-17,
20, 21).
The management of oropharyngeal candidosis in human immunodeficiency
virus (HIV)-positive patients remains poorly standardized. Topical
antifungal agents may be effective, but they are often unpalatable and
their use can be inconvenient. Ketoconazole, fluconazole, and
itraconazole are systematically active oral agents with proven activity
against Candida infections in patients with AIDS (7, 18). Some HIV-positive patients have a lower than normal
capability to absorb ketoconazole, as is the case with itraconazole,
the levels of which that are achieved in plasma are unpredictable (3, 19). Thus, fluconazole is being widely used for the
treatment of oropharyngeal candidosis, but it has increasingly been
associated with the selection of resistant strains of
Candida species (2, 12). D0870 offered the
potential of being a safe compound with activity against
fluconazole-resistant strains and enhanced activity against
fluconazole-susceptible strains.
The preclinical evaluation of D0870 has shown it to be extensively
metabolized in rats and cynomolgus monkeys but to have a less complex
metabolite profile in dogs. Prior to the start of the study none of the
metabolites of D0870 had been tested for bioactivity. D0870 has also
been demonstrated to be both an enzyme inducer and an inhibitor of
P-450 and to be highly bound (98%) to human plasma proteins. The
absolute bioavailability of D0870 was high and ranged from 56 to 60%
in male cynomolgus monkeys and male dogs to 80 to 100% in female and
male rats. In the safety evaluation, D0870 exhibited nonlinear kinetics
with a decrease in clearance from plasma and a consequent increase in
the terminal elimination half-life (t1/2) for
both increasing dose and duration of dosing. However, in an initial
clinical study, ascending single oral doses in a cyclodextrin solution
were given to healthy human volunteers on a milligram-per-kilogram
basis, with the doses ranging from 0.042 to 2.86 mg/kg of body weight
(2 to 190 mg). This trial showed that the mean elimination
t1/2 from plasma was 3.3 days (range, 1.1 to 8.0 days) and that the exposure to D0870 was in proportion to the increase
in dose based on the maximum concentration of drug in serum
(Cmax) and the area under the concentration-time curve (AUC) from time zero to infinity (AUC0- The aims of the trial described here were to investigate two
potentially clinically relevant multiple-dose regimens of D0870 considered suitable for use in the treatment of oropharyngeal candidosis caused by fluconazole-susceptible and -resistant strains to
assess the tolerability, safety, and pharmacokinetics of these regimens. In studies with D0870 administered orally to cynomolgus monkeys, increases in the QT and the corrected QT (QTc)
intervals were clearly related to the dose and the level in blood. This increases in the QT and QTc intervals are fully reversible
following the withdrawal of D0870. These findings were also observed in studies with dogs. Hence, during this study electrocardiograms (ECGs)
were monitored closely. The trial has been conducted with HIV-positive
subjects because it was predicted that D0870 would have a major
clinical use in this group of subjects, in whom D0870 might have
pharmacokinetic characteristics (related to absorption and metabolism)
which differ from those in normal, healthy subjects.
Study design.
The present study was a single-center, open,
ascending-oral-dose, nonrandomized trial. Initially, HIV-positive
volunteers received an initial loading dose of 50 mg of D0870 followed
by four once-daily maintenance doses of 10 mg. A further group of HIV-positive subjects received an initial 200-mg loading dose of D0870,
followed by four daily maintenance doses of 25 mg. The dosing of the
second group could be initiated only if no safety issues had been
identified during the previous dosings.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Pharmacokinetics of Two Multiple-Dosing Regimens of D0870 in
Human Immunodeficiency Virus-Positive Patients: a Phase I
Study
ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
). A further study demonstrated that the bioavailabilities of D0870 administered as tablets or in a cyclodextrin solution are comparable (mean ratio, 0.91; 95% confidence interval, 0.75 to 1.12)
(22).
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
Subjects. HIV-positive subjects volunteering to take part in the trial could be included if they were males, were between 18 and 62 years of age, and had a normal ECG (resting heart beat of between 45 and 100 beats per minute and a QTc interval of less than 450 ms). They were excluded from the trial in case of previous intolerance to azoles; a history or presence of gastrointestinal, hepatic, or renal disease or some other condition known to interfere with the absorption, distribution, or excretion of drugs; an acute illness during the previous 2 weeks; or a history of alcohol or drug abuse.
Eighteen HIV-positive male volunteers entered the trial. They had a mean age of 40.6 years (range, 28 to 63 years). The mean weight was 69.3 kg (range, 51.5 to 92.8 kg), and the mean height was 173.7 cm (range, 159.0 to 189.5 cm). The volunteers were clinically assessed for disease status and were assigned to the following CDC categories: A (n = 4), B (n = 13), and C (n = 1). The mean CD4 cell count was 276 cells/mm3 (range, 49 to 659 cells/mm3). Nine subjects were entered into part I of the study and nine subjects were entered into part II of the study. The following concomitant medications were prohibited: other investigational drugs, cytotoxic agents, agents known to affect cardiac rhythm or ECG at normal doses, systemic antifungal agents, stavudine, antacids, H2 antagonists, anticholinergic agents, and agents other than cotrimoxazole or aerosolized pentamidine for prophylaxis for Pneumocystis carinii pneumonia. Agents known to induce cytochrome P-450 (rifampin, rifabutin, phenytoin, phenobarbitone, carbamazepine) or to interact with azoles were also prohibited. D0870 was metabolized in cultured human hepatocytes to form two quantifiable metabolites (metabolites A and B). The formation of metabolite B was not reduced by any of the model P-450 enzymes. However, the generation of metabolite A was abolished in the presence of ketoconazole and quinidine; although a potent inhibitor of CYP 2D6, quinidine is metabolized by CYP 3A4 and therefore may act as a competitive inhibitor of this isozyme, suggesting that CYP 3A4 may have been involved in the formation of metabolite A. However, omeprazole, which is also a substrate of CYP 3A4, had no inhibitory effect and, in contrast, appeared to potentiate the metabolism of D0870. Although the mechanism by which this activation occurs is not known, similar effects on CYP 3A4 activities have been described previously in hepatic microsomes and may involve an allosteric interaction. While it is possible that CYP 2D6 is also involved in the formation of metabolite A, the effect of ketoconazole indicates a more prominent role for CYP 3A4 in the metabolism of D0870, which may therefore be affected to some degree by an interaction with coadministered agents that induce or inhibit CYP 3A4. Since the metabolic route apparently mediated by CYP 3A4 is not the major in vitro clearance pathway, the clinical significance of any such effect is likely to be limited. The extent of D0870 metabolism achieved during this prolonged in vitro incubation was still very low. It is possible, therefore, that for many compounds which have long in vivo half-lives, this type of in vitro approach will not yield any valuable information and the enzymes involved in the metabolism of D0870 may best be deduced from clinical interaction studies. The eligibility of each volunteer was established before allocation to trial therapy. All participants signed an informed, witnessed consent to participate in the study. Volunteers were required to fast from midnight on the evening before administration of the first and last doses of D0870 and to abstain from consuming alcohol, liquorice, and grapefruit for the duration of the trial. D0870 was supplied as white, biconvex, film-coated 25- and 10-mg tablets for oral use. Drugs were dispensed by the study nurse. All unused drugs were returned to the study nurse.Patient monitoring. Volunteers were confirmed as HIV seropositive before entering the trial. The stage of HIV infection was assessed by using the CD4 lymphocyte count and the Centers for Disease Control and Prevention clinical categories. A full medical history was taken for each volunteer, and a physical examination was performed before therapy was begun. A 12-lead ECG and a 24-h Holter monitor were performed, and all hematological and biochemical parameters were also measured before entry into the trial.
The concentrations of D0870 in plasma were estimated with blood samples taken on days 1 and 5 before dosing and 1, 2, 3, 4, 6, 8, 10, 12 and 18 h after dosing; on days 2, 3, 4, and 5 before dosing; and on days 6, 7, 9, 12, and 19 after dosing (namely, 24 to 336 hours after administration of the last dose). If the plasma D0870 levels remained above the limit of detection (2.01 ng/ml) 14 days after administration of the last dose (day 19), further samples were taken at fortnightly intervals until the level of D0870 in plasma was predicted to have fallen below the limit of detection. Samples for pharmacokinetic analysis were centrifuged at 1,000 × g for 10 min (4°C), and the plasma was deep frozen and stored at
20°C until it
was analyzed. At 20°C D0870 was found to be stable for up to 1 month in human plasma.
The samples were analyzed for D0870 by high-performance liquid
chromatography with UV detection by the following procedure. To an
aliquot (1 ml) of each unknown was added an internal standard (ZM196144), borate buffer (1 ml; pH 10), and methyl-tertiary butyl ether (5 ml). After shaking on a reciprocating shaker for 10 min and
centrifuging at 1,000 × g for 5 min at 5°C to
separate the phases, the organic layer was removed, placed in a clean
tube, and evaporated to dryness under oxygen-free nitrogen at 25°C. The extracted dry residue was reconstituted in a suitable amount of
mobile phase and was injected onto the following high-performance liquid chromatography system: a Hichrom RPB column (150 mm by 4.6 mm
[inner diameter]) with a reverse phase deactivated with a base and a
mobile phase of degassed acetonitrile-water (55/45) plus 1 ml of
trifluoroacetic acid per liter. The flow rate was 1 ml/min. The
detector was a variable-wavelength UV spectrophotometer set at 292 nm.
A calibration series covering the expected concentration range was
constructed in control human plasma by adding known amounts of D0870
and an amount of internal standard equivalent to the amount added to
the unknowns and extracted together with each batch of unknowns. The
data were captured and processed by using the VG Multichrom (version 2)
laboratory data capture system incorporating a 1/x weighting
factor to the calibration regression, where x is the known
concentration of each calibration. Unknown concentrations of D0870 were
determined by comparison of the peak height ratios to the calibration
series. The chromatography was free of any endogenous or exogenous
components at the relevant retention times and had a total assay
variation of less than 10% for concentrations in excess of the limit
of detection of 2.01 ng/ml, for which it was 15%.
The following pharmacokinetic parameters were assessed:
Cmax on days 1 and 5, AUC0-24 on
days 1 and 5, t1/2 after administration of the
last dose, and the accumulation ratio based on the
AUC0-24. Cmax and the time to
Cmax (Tmax) were taken
directly from the data. The AUC0-24s on days 1 and 5 were
calculated by the trapezoidal rule, with the accumulation ratio being
the ratio of the AUC0-24 on day 5 to the
AUC0-24 on day 1. The elimination rate constant
(kel) was calculated by log-linear regression analysis from those points considered to determine the first-order terminal elimination phase (r2 > 0.90),
and the t1/2 was calculated from the
relationship 0.693/kel.
All adverse events, either observed or reported by the volunteer either
spontaneously or in response to direct questions, were recorded. Blood
samples were taken for routine clinical chemistry and hematological
screening. These tests were performed before the administration of the
first dose, before the administration of the second dose (i.e., 24 h after the administration of the first dose), after the administration
of the last dose (day 6), and on days 12 and 19 (i.e., 7 and 14 days
after the administration of the last dose). A freshly voided urine
sample was taken at the same time points for estimation of glucose, pH,
bilirubin, albumin, blood, and ketone levels. If any clinically
significant changes in a variable occurred, follow-up samples were
taken 1 week later and samples were retested until the value for that variable normalized or returned to the pretherapy baseline level.
A resting 12-lead ECG was obtained (after the subject had been in the
supine position for 10 min) at each of the following time points:
before administration of the first dose; 4, 8, 12, and 24 h after
administration of the first dose; predosing on days 3 and 4; before and
4, 8, 12, and 24 h after the administration of the last (fifth)
dose; and 7 and 14 days after the administration of the last dose.
The volunteers remained in the research unit for 24 h after the
administration of each of the first and last doses of D0870 and for
longer if necessary. Volunteers were discharged from the unit only
after the investigator was satisfied that there were no ECG changes and
that the volunteer was fit for discharge. Continuous ambulatory ECG
(Holter monitoring) was performed for a 24-h period before entry into
the trial and for 24 h after the administration of first and last
doses of D0870. A lead II real-time ECG was displayed for 8 h
postdosing on days 1 and 5 and was monitored by a physician or research
nurse.
A posttreatment medical examination was performed within 4 weeks after
collection of the last sample.
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RESULTS |
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Pharmacokinetics. The mean values of the pharmacokinetic parameters obtained following dosing with D0870 on days 1 and 5 are presented in Table 1. A single loading dose of 50 mg of D0870 resulted in a mean Cmax of 107 ng/ml. Tmax ranged from 3 to 12 h. The concentrations of D0870 in plasma were relatively well maintained by the 10-mg once-daily dosing regimen, as seen by the similar AUC0-24 values obtained following dosing on days 1 and 5 and a mean accumulation ratio of close to unity (0.90). The terminal t1/2 of D0870 in plasma following the administration of the last dose ranged from 23 to 85 h (mean, 49 h). The administration of a single loading dose of 200 mg of D0870 resulted in a Cmax of 431 ng/ml. Tmax ranged from 3 to 24 h. The concentrations in plasma were again maintained by the 25-mg once-daily dosing regimen as seen by the similar AUC0-24 values following dosing on days 1 and 5 and a mean accumulation ratio again close to unity (1.17). The terminal plasma t1/2 of D0870 in plasma following the administration of the last dose ranged from 34 to 137 h (mean, 71 h).
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Safety. D0870 was well tolerated. No serious adverse events were experienced by the volunteers during the course of the trial, and all volunteers completed the trial. Eight volunteers in the trial had a total of 15 adverse events; these comprised abscess, fever, headache, diarrhea, nausea, thrombocytopenia, elevated alanine aminotransferase level, and elevated aspartate aminotransferase level. Most of these adverse events were reported in the follow-up period after the administration of the final dose of D0870. No adverse events were considered to be related to the study drug. All adverse events had resolved by the end of the trial. No changes in any of the hematology, clinical chemistry, or urinalysis parameters were considered to be related to dosing with D0870. A review of the ECG and Holter monitoring parameters by an independent cardiologist did not identify any significant abnormalities during the trial. There were no deaths during the trial.
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DISCUSSION |
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Discussion
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D0870 is a triazole antifungal agent which belongs to the same
structural class as fluconazole and itraconazole. D0870, in common with
the related triazoles, exerts its antifungal activity through selective
inhibition of the fungal P-450-dependent 14-
-demethylase step in
ergosterol biosynthesis, resulting in a fungistatic mechanism. In vitro
D0870 is highly active against a wide range of fungi, including various
Candida species, Aspergillus species,
Cryptococcus neoformans, Histoplasma capsulatum,
Blastomyces dermatitidis, Coccidioides immitis,
Sporothrix schenckii, Trichophyton species, and
Pseudallescheria boydii (14-16, 21).
D0870 is also active in vitro against fluconazole-resistant Candida species (20). D0870 has been shown to be active in various animal models including infections with C. albicans, Candida parapsilosis, Candida krusei, and Candida lusitaniae (1, 10, 11, 17, 21). Other infections such as cryptoccosis, histoplasmosis, coccidioidomycosis, and blastomycosis in immunocompromised mice have been treated effectively by D0870 (6, 13, 17).
The long t1/2 of D0870 in humans (1 to 8 days), determined after the administration of single oral doses to normal, healthy subjects, suggested that therapeutic levels of D0870 will be most rapidly achieved and maintained by means of a loading dose-maintenance dose regimen. The doses and duration of dosing used in this trial were designed to be potentially clinically effective against fluconazole-susceptile and fluconazole-resistant strains causing oropharyngeal candidosis. On the basis of the t1/2 observed in the study, loading dose-maintenance dose ratios of 5 to 1 and 8 to 1 were chosen such that patients in whom the t1/2 of D0870 was at each end of the t1/2 range would not have significant over- or underexposure over the 5-day dosing period. An additional aim of this study was to assess if the pharmacokinetics of D0870 in HIV-positive subjects was significantly different from the pharmacokinetics in normal, healthy subjects. Plasma concentration-time data after oral dosing of D0870 to normal, healthy subjects (22) was modeled with a one-compartment oral model with a lag time. Parameters from this model were then used to predict the concentrations in plasma resulting from the dosing regimens chosen for this trial, and these were compared to the concentrations that were actually determined.
A mean Cmax of 107 and 431 ng/ml after the administration of single doses of 50 and 200 mg, respectively, compared well to the predicted values of 155 and 460 ng/ml, respectively. Tmax was variable and on occasion occurred as late as 24 h after dosing, presumably reflecting the slow and variable absorption of D0870. Similarly, on day 5 the range of Cmaxs observed (34 to 174 ng/ml) after the administration of 50 mg of D0870 followed by the administration of 10 mg/day for 4 days compared well to the predicted range of D0870 (52 to 135 ng/ml). The range of terminal t1/2s seen in HIV-positive subjects after the administration of multiple doses (1 to 6 days) was also similar to the range seen in normal, healthy subjects after the administration of single doses. Terminal t1/2s were longer after the higher-dose regimen. It is probable that this reflects the trial design and subject randomization rather than evidence of dose-dependent kinetics. In addition, the accumulation in individual subjects seen over the dosing period, which was within acceptable limits, correlated well with the final terminal t1/2. Within each regimen similar exposures, as assessed by the AUC over the doing interval, were achieved between days 1 and 5.
In summary, there was no evidence of nonlinear kinetics following the administration of multiple doses of D0870 and no evidence of a difference in the pharmacokinetics of D0870 in HIV-positive subjects compared to that in normal, healthy subjects. In addition, the exposures were comparable on days 1 and 5, and D0870 was well tolerated, with no safety issues. This study supported the further investigation of these regimens in HIV-positive patients with oropharyngeal candidosis caused by fluconazole-susceptible and fluconazole-resistant strains. Data from these later studies indicated that no safe and effective dosing regimen could be established, and the development of D0870 was discontinued outside Japan.
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FOOTNOTES |
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* Corresponding author. Mailing address: Division of Infectious Diseases (PL5), C.H.U. Saint-Pierre, rue Haute 322, B-1000 Brussels, Belgium. Phone: 32.2/535.41.30. Fax: 32.2/539.36.14. E-mail: nclumeck{at}ulb.ac.be.
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Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, April 1998, p. 903-906, Vol. 42, No. 4
0066-4804/98/$04.00+0
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