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Antimicrobial Agents and Chemotherapy, September 1998, p. 2380-2384, Vol. 42, No. 9
University of California, San Francisco, and
San Francisco General Hospital, San Francisco,
California1;
Johns Hopkins University
School of Medicine, Baltimore, Maryland2;
and
Gilead Sciences, Inc., Foster City,
California3
Received 12 November 1997/Returned for modification 14 February
1998/Accepted 18 June 1998
9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a
nucleotide analogue with potent antiretroviral activity in
vitro and in simian models. A randomized, double-blind,
placebo-controlled, dose-escalation clinical trial of intravenous PMPA
monotherapy was conducted in 20 human immunodeficiency virus
(HIV)-infected adults with CD4 cell counts of Nucleoside analogues, such as
zidovudine and d4T, require intracellular phosphorylation to an
active triphosphate metabolite. The expression of the
intracellular nucleoside kinase responsible for the initial
phosphorylation is low in resting lymphocytes and
macrophages/monocytes, thus limiting the activity of such nucleoside
analogues in these important cellular targets of human immunodeficiency
virus (HIV) infection (2, 7, 10). In contrast, nucleoside
monophosphate (nucleotide) analogues do not require intracellular
phosphorylation by the nucleoside kinase and thus may possess greater
activity in a broader range of cell types (3).
9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a
nucleotide analogue with potent antiretroviral activity. In a
4-week study of adult macaques chronically infected with simian
immunodeficiency virus (SIV), once-daily subcutaneous injections of
PMPA (30 to 75 mg/kg of body weight/day) resulted in a decline in
plasma SIV RNA levels from a baseline of 2 to 3 log10
copies/ml (12). With continued dosing, this effect was
sustained for greater than 1 year (14). In macaques, 4 weeks
of once-daily subcutaneous injections of PMPA (30 mg/kg/day) initiated
as late as 24 h after intravenous inoculation of SIV prevented
infection (13).
In preclinical toxicity studies, PMPA at effective doses appeared
to be safe. Nephrotoxicity, characterized by proximal convoluted tubule
degeneration, was the principal toxicity when PMPA was infused at
very high doses (>75 mg/kg/day). In vivo and in vitro, the active
metabolite of PMPA has an intracellular half-life of 12 to 15 h in
activated lymphocytes and 33 to 50 h in resting lymphocytes, thus
suggesting that once-a-day dosing regimens may be possible
(11). Finally, preliminary data indicate that PMPA does not
select for high-level resistance during in vitro propagation of the HIV
in the presence of the drug (4). Considering these favorable
preclinical results, a randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was
initiated in 20 HIV-infected adults.
(Part of this research was presented at the International
Conference on Antiviral Research, Atlanta, Ga., April 1997, and at the Sixth European Conference on the Clinical Aspects and
Treatment of HIV Infection, Hamburg, Germany, October
1997.)
Study design.
Eligible subjects were men or women aged 18 to
60 years with documented HIV infection, plasma HIV RNA levels of
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Safety, Pharmacokinetics, and Antiretroviral Activity of
Intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a
Novel Anti-Human Immunodeficiency Virus (HIV) Therapy, in
HIV-Infected Adults
ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
200
cells/mm3 and plasma HIV RNA levels of 10,000 copies/ml.
Two dose levels were evaluated (1 and 3 mg/kg of body weight/day). Ten
subjects were enrolled at each dose level (eight randomized to receive PMPA and two randomized to receive placebo). On day 1, a single dose of
PMPA or placebo was administered by intravenous
infusion. Beginning on study day 8, PMPA or placebo was administered
once daily for an additional 7 consecutive days. All subjects tolerated dosing without significant adverse events. Mean peak serum PMPA concentrations were 2.7 ± 0.9 and 9.1 ± 2.1 µg/ml in the
1- and 3-mg/kg cohorts, respectively. Serum concentrations declined in a biexponential fashion, with a terminal half-life of 4 to 8 h. At
3 mg/kg/day, a single infusion of PMPA resulted in a 0.4 log10 median decline in plasma HIV RNA by study day 8. Following 7 consecutive days of study drug administration thereafter,
the median changes in plasma HIV RNA from baseline were 
1.1, 0.6,
and 0.1 log10 in the 3-mg/kg/day, 1-mg/kg/day, and placebo
dose groups, respectively. Following the final dose in the 3-mg/kg/day
cohort, the reduction in HIV RNA was sustained for 7 days before
returning toward baseline. Further studies evaluating an oral prodrug
of PMPA are under way.
INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References
10,000 copies/ml, and CD4 cell counts of 200 cells/mm3.
Other inclusion criteria included serum creatinine concentrations of
1.5 mg/dl, calculated creatinine clearance (CLCR) of 50
ml/min (determined by the Cockcroft-Gault formula), 1+ proteinuria, total bilirubin concentrations of 1.5 mg/dl, hepatic transaminases of
3 times the upper limit of normal, absolute neutrophil counts of
1,000 cells/mm3, platelet counts of
75,000/mm3, hemoglobin concentrations of 9.0 g/dl, and
prothrombin times of <1.2 times the upper limit of normal. A negative
serum pregnancy test was required at the time of enrollment for women
of childbearing age. Subjects with positive serum tests for hepatitis B
surface antigen were excluded, as were those with active, serious
infections.
Safety and efficacy analyses. Subjects underwent a qualifying physical examination 24 h prior to the first dose and had directed regular physical examinations through study day 42. Assessments of serum chemistries, hematology, coagulation parameters, and urinalyses were performed regularly during study drug administration and on days 21, 28, and 42 after study drug discontinuation.
Blood and plasma samples for T-cell subset analysis (CD4 and CD8) and HIV RNA assays were obtained prior to the dose on days 1, 2, 4, 8, and 11 and immediately after the day 14 dose. Final plasma HIV RNA determinations were performed on days 21 and 28. For HIV RNA analysis, plasma was obtained by centrifugation within 4 h of blood collection and stored at70°C. Samples were shipped to a central
laboratory and analyzed as one batch by reverse transcriptase quantitative polymerase chain reaction assay (Amplicor; Roche Diagnostics Inc.; lower limit of quantification, 400 copies/ml).
Symptoms, signs, and laboratory abnormalities were recorded with a
graded toxicity scale based on the AIDS Clinical Trials Group's Table
for Grading Severity of Adult Adverse Events. In general, mild symptoms
were classified as grade I, moderate symptoms as grade II, severe
symptoms as grade III, and life-threatening symptoms as grade IV. The
relationship of an adverse event to the study medication was assessed
by the treating investigator and was done without knowledge of
treatment assignment to PMPA or placebo. Subjects with grade III or IV
events thought by the investigator to be drug related were removed from
study. For grade III or IV events not considered to be study drug
related, the drug was withheld until the event resolved. At the
discretion of the investigators, subjects with grade II events could
remain on the study drug.
Pharmacokinetic analyses.
Prior to the first dose, subjects
were admitted to an inpatient research center. From midnight prior to
the first dose until 2 h after the first dose, subjects were
maintained in a fasting state (except water ad lib). On day 1, serum
for pharmacokinetic analysis was obtained at 0 h (predose),
0.5 h (mid-infusion), and 1 h (end of infusion). Thereafter,
serum was obtained at hours 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24. A
similar inpatient pharmacokinetic assessment was performed following
the final dose (day 14). At each time point, approximately 10 ml of
blood was obtained; serum was separated and stored at 20°C.
). The steady state volume of distribution (VSS) was calculated as mean residence time × CL. Urine samples were collected for 72 h following the start
of the PMPA infusion. The concentration of PMPA in serum at the end of
the 72-h urine collection period (C72) was
calculated as Clast × e[
beta × (72 tlast)], where
Clast is the last quantifiable concentration of
PMPA in serum and tlast is the time of the last
quantifiable concentration of PMPA in serum. The area under the
serum concentration-time curve up to the end of the urine collection
period, AUC0-72, was calculated as AUC0- (C72/beta). The renal clearance (CLR) of PMPA following the first intravenous
administration was calculated as (U0-72 × 1,000)/(AUC0-24 × Wt) where U0-72 is the
total milligrams of PMPA excreted in the urine during the entire urine
collection and Wt is the body weight of the patient in kilograms. The
corresponding CLR on day 14 of the study was calculated as
(U0-24 × 1,000)/(AUCSS × Wt), where AUCSS is the steady-state AUC. The cumulative amount of
PMPA excreted at the end of each urine collection period,
U0-t, was calculated as the sum of the amounts
excreted in all previous collection periods. The cumulative percentage
of the dose excreted at the end of each collection period was
calculated as 100 × (U0-t/dose).
Statistical analyses. The distribution of all summary data for each analyzed variable was assessed for normality. Statistical analyses were performed for comparisons of the pooled placebo group to each active drug group. All P values were two sided. The significance level of all tests was set at 5%. Baseline characteristics were compared among dose groups by analysis of variance for continuous variables and Pearson's chi-square test for categorical variables. Statistical comparisons of changes in plasma HIV RNA levels through the completion of the study period were assessed by absolute change from baseline. Changes in CD4 cell counts and plasma HIV RNA levels between the placebo and each active dose group were compared by the Wilcoxon rank-sum test.
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RESULTS |
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Materials & Methods
Results
Discussion
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Baseline characteristics. Between October 1996 and January 1997, 20 HIV-infected subjects were enrolled (10 at the 1-mg/kg dose level and 10 at the 3-mg/kg dose level, with 2 subjects in each dosing group receiving placebo). The baseline characteristics in the placebo group and the two treatment groups are shown in Table 1. Seventeen (85%) of the subjects were male. Each of the three female subjects in the study was randomized to receive placebo. The median age of the study subjects was 39 years. The median CD4 cell count at entry for the entire study group was 363 cells/mm3 (range, 133 to 1,259), while the median baseline plasma HIV RNA level was 4.7 log10 copies/ml (range, 3.5 to 5.6) (Table 1).
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Pharmacokinetics. Pharmacokinetic data from both dose groups are outlined in Table 2 and Fig. 1. For the first dose cohort (1 mg/kg/day), a single infusion of PMPA resulted in a maximum serum concentration (Cmax) of 2.7 ± 0.9 µg/ml. Serum concentrations declined in an apparently biexponential fashion with a terminal half-life of 4.5 ± 0.6 h. All subjects that were given a single 1-mg/kg dose had detectable levels of PMPA 12 h later. Administration of a single 3-mg/kg dose resulted in a serum Cmax of 9.1 ± 2.1 µg/ml. Serum PMPA concentrations declined in a biexponential manner with a terminal half-life of 7.1 ± 1.3 h. All subjects in the higher dose cohort displayed quantifiable serum levels for up to 24 h after the first dose. The apparent difference in half-life at the 1.0- and 3.0-mg/kg dose levels may be artifactual, resulting from the constraints of the bioanalytical method (serum concentrations were not quantifiable beyond 12 h postdosing at the 1.0-mg/kg dose).
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Safety and tolerability. All 20 subjects completed dosing as planned. All patients reported at least one adverse event during the study period; 14 patients (70%) had at least one adverse event that was felt to be possibly or probably related to study drug administration. No life-threatening events occurred during the study. Events graded as moderate or severe in toxicity and considered possibly or probably related to the study drug occurred in four patients and included headache, fatigue, proteinuria, neutropenia, and abdominal pain. These were all graded moderate events with the exception of the proteinuria and neutropenia, which were each graded severe and which occurred in a single placebo recipient. Distribution of the events relative to dose group is presented in Table 3. There was no apparent relationship between event frequency or severity and dose.
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T-cell subsets. After completion of dosing with PMPA (i.e., study day 14), there was a median increase in CD4 cell count from baseline of 27 and 32 cells/mm3 in subjects in the 1- and 3-mg/kg dose groups, respectively, compared to a median decrease of 65 cells in placebo recipients. This difference between the active and placebo groups did not reach statistical significance (P = 0.2 for the 1-mg/kg-dose group versus a placebo; P = 0.2 for the 3-mg/kg-dose group versus a placebo; Wilcoxon rank-sum tests).
HIV RNA levels.
After a single intravenous infusion of
PMPA, there was a moderate decrease in plasma HIV RNA
levels at day 4 (median log10 declines of 0.2
and 0.2 copies/ml in the 1- and 3-mg/kg dose groups,
respectively; see Fig. 2). At day 8, just prior to initiation of
continued daily dosing, there was a median decrease from baseline of
0.15 log10 copies/ml in the 1-mg/kg treatment group, and a median decrease of 0.4 log10 copies/ml in the 3-mg/kg
treatment group, compared to a median increase of 0.05 log10 copies/ml in the placebo group
(P = 0.4 and P = 0.07 for the 1- and
3-mg/kg groups versus a placebo, respectively).
0.6, and 1.1 copies/ml in
the placebo group and 1.0- and 3.0-mg/kg/day dose groups, respectively (P = 0.009 for the 1.0-mg/kg-dose group versus a
placebo and P = 0.03 for the 3.0-mg/kg-dose group
versus a placebo). The median reduction in plasma HIV RNA levels was
not significantly different between the two active treatment groups
(P = 0.4).
Seven days after PMPA was discontinued (study day 21), the median
plasma HIV RNA level began to return towards baseline in the
1-mg/kg-dose group. However, in the 3-mg/kg-dose group, the median
log10 plasma HIV RNA level remained stable at 1.1 copies/ml below baseline on day 21, eventually returning to near baseline by day
28 (Fig. 2). As illustrated in Fig.
3, there appeared to be a correlation
between the antiviral response after 7 consecutive days of dosing
(i.e., the median decrease in plasma HIV RNA on study day 14) and the
exposure to PMPA (i.e., the median AUC on study day 1).
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DISCUSSION |
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Materials & Methods
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Discussion
References
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In this phase I/II blinded multicenter clinical trial, short-term use of the nucleotide analogue PMPA administered intravenously to HIV-infected subjects was safe, well tolerated, and effective in reducing plasma HIV RNA levels.
In preclinical studies, administration of PMPA as monotherapy was associated with a decline in plasma SIV RNA levels in chronically infected macaques of >2 log10 copies/ml (12, 14). The clinical data generated by this first study of PMPA in humans demonstrated a dose-dependent, statistically significant decrease in plasma HIV RNA levels when PMPA was administered eight times over a 2-week period. At the higher dose studied (3 mg/kg/day), median plasma HIV RNA levels declined by greater than 90% (median log10 decrease, 1.1 copies/ml). This magnitude of the antiviral effect is comparable to that observed after limited dosing of other potent antiretroviral therapies, including HIV-1 protease inhibitors (5, 8). Accruing data suggest that declines in plasma HIV RNA levels are highly predictive of clinical outcome (9).
At both doses of PMPA studied, viral load continuously decreased during the PMPA 7-day consecutive treatment period (days 8 to 14). Since the nadir was not clearly reached, a more potent effect may be obtained with continued administration of PMPA. Moreover, although statistical significance was not achieved, there appeared to be an anti-HIV effect seen following a single dose of PMPA (median decline in plasma HIV RNA levels at 3 mg/kg, 0.4 log10 copies/ml). This effect persisted for up to 7 days after a single infusion. Similarly, when PMPA (3 mg/kg/day) was discontinued (after 7 days of continuous dosing), HIV RNA suppression persisted for up to 1 week. The sustained depression in plasma HIV RNA observed after drug discontinuation is consistent with the prolonged intracellular half-life of the intracellular phosphorylated drug, which has been found to be 12 to 50 h in activated and resting peripheral blood lymphocytes, respectively, in vivo (11).
PMPA administered parenterally was well tolerated in this study. All subjects completed dosing without interruptions. The most frequent adverse events were mild and transient and included headache, dizziness, fatigue, and nausea. The only moderate (grade II) adverse events thought to be related to PMPA were transient episodes of nausea, fatigue, and abdominal pain, each occurring in one patient. All symptoms resolved despite continuous administration of drug. No clinically significant laboratory abnormalities were noted during the trial.
There was a significant increase in the AUC of PMPA in serum after 14 days of dosing at 3.0 mg/kg/day. A possible explanation is that clearance of PMPA decreased over the course of the study. An alternative explanation, however, is that of gradual accumulation of a fraction of the dose due to a slowly equilibrating compartment with a long half-life. Analysis of the serum data for 3.0 mg of PMPA/day with an open three-compartment model with multiple dosing (data not shown) gave a good fit of the data with a terminal half-life of 31 h. This compartment may represent the prolonged half-life of the intracellular phosphorylated drug, as discussed above.
In studies to date, selection of resistance mutations in the reverse transcriptase gene in vitro has been relatively difficult, and high-level resistance has not been observed (4). Similarly, PMPA did not select for high-level viral resistance in SIV-infected macaques (14). Since the emergence of resistance to PMPA was not analyzed in the present study due to the short duration of dosing, future studies will need to confirm a low propensity for development of resistance during more prolonged dosing.
In summary, in this phase I/II clinical study, intravenous PMPA appeared to be safe and well tolerated. Parenterally administered PMPA resulted in a significant reduction in plasma HIV RNA levels, even after a single infusion. An oral prodrug of PMPA, bis(isopropyloxymethylcarbonyl) PMPA, has been developed (1, 11) and is currently under clinical evaluation (6). The greater lipophilicity of the oral prodrug than the PMPA the parent compound has been shown in preclinical models to result in a greater ability to cross cellular membranes and therefore enhances oral bioavailability. Future plans are to evaluate the safety and efficacy of long-term dosing of PMPA when administered orally.
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ACKNOWLEDGMENT |
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This study was supported by Gilead Sciences, Inc.
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FOOTNOTES |
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* Corresponding author. Mailing address: 995 Potrero Ave., San Francisco General Hospital, San Francisco, CA 94110. Phone: (415) 476-4082, ext. 404. Fax: (415) 476-6953. E-mail: sdeeks{at}sfaids.ucsf.edu.
Present address: ViroLogics, Inc., South San Francisco, CA.
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Discussion
References
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Antimicrobial Agents and Chemotherapy, September 1998, p. 2380-2384, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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van Gelder, J., Deferme, S., Naesens, L., De Clercq, E., van den Mooter, G., Kinget, R., Augustijns, P.
(2002). Intestinal Absorption Enhancement of the Ester Prodrug Tenofovir Disoproxil Fumarate through Modulation of the Biochemical Barrier by Defined Ester Mixtures. Drug Metab. Dispos.
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Hammer, S. M., Vaida, F., Bennett, K. K., Holohan, M. K., Sheiner, L., Eron, J. J., Wheat, L. J., Mitsuyasu, R. T., Gulick, R. M., Valentine, F. T., Aberg, J. A., Rogers, M. D., Karol, C. N., Saah, A. J., Lewis, R. H., Bessen, L. J., Brosgart, C., DeGruttola, V., Mellors, J. W., for the AIDS Clinical Trials Group 398 Study Team,
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Harrigan, P. R., Miller, M. D., McKenna, P., Brumme, Z. L., Larder, B. A.
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Barditch-Crovo, P., Deeks, S. G., Collier, A., Safrin, S., Coakley, D. F., Miller, M., Kearney, B. P., Coleman, R. L., Lamy, P. D., Kahn, J. O., McGowan, I., Lietman, P. S.
(2001). Phase I/II Trial of the Pharmacokinetics, Safety, and Antiretroviral Activity of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-Infected Adults. Antimicrob. Agents Chemother.
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Lifson, J. D., Rossio, J. L., Arnaout, R., Li, L., Parks, T. L., Schneider, D. K., Kiser, R. F., Coalter, V. J., Walsh, G., Imming, R. J., Fisher, B., Flynn, B. M., Bischofberger, N., Piatak, M. Jr., Hirsch, V. M., Nowak, M. A., Wodarz, D.
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Van Rompay, K. K. A., Miller, M. D., Marthas, M. L., Margot, N. A., Dailey, P. J., Canfield, D. R., Tarara, R. P., Cherrington, J. M., Aguirre, N. L., Bischofberger, N., Pedersen, N. C.
(2000). Prophylactic and Therapeutic Benefits of Short-Term 9-[2-(R)-(Phosphonomethoxy)Propyl]Adenine (PMPA) Administration to Newborn Macaques following Oral Inoculation with Simian Immunodeficiency Virus with Reduced Susceptibility to PMPA. J. Virol.
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van Rompay, K. K. A., Cherrington, J. M., Marthas, M. L., Lamy, P. D., Dailey, P. J., Canfield, D. R., Tarara, R. P., Bischofberger, N., Pedersen, N. C.
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van Rompay, K. K. A., Dailey, P. J., Tarara, R. P., Canfield, D. R., Aguirre, N. L., Cherrington, J. M., Lamy, P. D., Bischofberger, N., Pedersen, N. C., Marthas, M. L.
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Johnson, A. A., Ray, A. S., Hanes, J., Suo, Z., Colacino, J. M., Anderson, K. S., Johnson, K. A.
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