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Antimicrobial Agents and Chemotherapy, July 1998, p. 1815-1818, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Pharmacokinetics of the Protease Inhibitor KNI-272 in Plasma and
Cerebrospinal Fluid in Nonhuman Primates after Intravenous Dosing
and in Human Immunodeficiency Virus-Infected Children after
Intravenous and Oral Dosing
Brigitta U.
Mueller,1,*
Barry D.
Anderson,1
Maureen Q.
Farley,1
Robert
Murphy,1
Judy
Zuckerman,1
Paul
Jarosinski,2
Karen
Godwin,1
Cindy L.
McCully,1
Hiroaki
Mitsuya,3
Philip A.
Pizzo,1 and
Frank M.
Balis1
Pediatric Branch1 and
Medicine Branch,3
National
Cancer Institute, and Pharmacy Department, Warren Grant Magnuson
Clinical Center,2 National Institutes of Health,
Bethesda, MD 20892
Received 19 August 1997/Returned for modification 7 February
1998/Accepted 27 April 1998
 |
ABSTRACT |
KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor
with potent activity in vitro. We studied the pharmacokinetics of
KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children
with HIV infection. Plasma and CSF were sampled over 24 h after
the administration of an intravenous dose of 50 mg of KNI-272 per kg of
body weight (approximately 1,000 mg/m2) to three nonhuman
primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a
phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m2 per dose given four times daily). The plasma
concentration-time profile of KNI-272 in the nonhuman primate model was
characterized by considerable interanimal variability and rapid
elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were
characterized by rapid elimination (clearance, 276 ml/min/m2; terminal half-life, 0.44 h), limited (12%)
and apparently saturable bioavailability, and limited distribution
(volume of distribution at steady state, 0.11 liter/kg). The
concentrations in plasma were maintained above a concentration that is
active in vitro for less than half of the 6-h dosing interval. There
was no significant increase in CD4 cell counts or decrease in p24
antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may
limit the drug's efficacy in vivo. It appears that KNI-272 will play a
limited role in the treatment of HIV-infected children.
| |
INTRODUCTION |
Protease inhibitors have become
increasingly important as part of the therapeutic options against human
immunodeficiency virus (HIV) infection. KNI-272 is a peptide-based
antiretroviral agent that inhibits the catalytic activity of the
HIV-1-specific aspartic protease (18) and that has
potent activity in vitro against a wide spectrum of HIV type
1 (HIV-1) and HIV-2 strains (6, 13). In preclinical
pharmacokinetic studies with rodents and dogs, concentrations in plasma
that exceeded the 50% effective concentration (EC50; 0.1 µM) were achieved and were maintained for several hours without
unacceptable toxicity (14, 15).
We evaluated the pharmacokinetics of KNI-272 after intravenous and oral
administration to children who were treated in a phase I trial. We
previously measured the levels of penetration of a number of
antiretroviral drugs into cerebrospinal fluid (CSF) in a nonhuman
primate model which has been predictive of the degree of penetration
into the CSF of humans (1-3, 7, 10). In the present study
we therefore evaluated the pharmacokinetics of KNI-272 in plasma and
CSF of this well-established animal model.
| |
MATERIALS AND METHODS |
Nonhuman primates. (i) Animals.
Three adult male rhesus
monkeys (Macaca mulatta) weighing 8.1, 9.3, and 11.2 kg,
respectively, were studied. The animals were group housed in accordance
with the Guide for the Care and Use of Laboratory Animals
(21) and received food and water ad libitum. Heparinized
blood samples were drawn from a saphenous or femoral venous catheter
(contralateral to the site of injection) prior to administration of the
dose and 5, 15, and 30 min and 1, 2, 4, 6, 8, 12, and 24 h after
administration of the dose. The plasma was immediately separated by
centrifugation and was frozen at 
70°C until it was assayed. For
animals CH980 and CH957, CSF was collected prior to administration of
the dose, 30 and 60 min after the beginning of the infusion, and 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 h after the end of the infusion
from a chronically indwelling subcutaneous Ommaya reservoir attached to
a 4th ventricular Pudenz catheter (20). For animal 608PR CSF
samples were obtained from a newly placed temporary lumbar catheter.
(ii) Drug formulation and administration.
The white powder
of KNI-272 was mixed in a ratio of 1:60 (wt:wt) with
hydroxypropyl-
-cyclodextrin (HPCD) (5a), reconstituted with 0.9% sodium chloride, and adjusted to a pH of 2.0 to 3.5 with
hydrochloric acid. The final concentration of this solution was 2.8 mg/ml. Prior to intravenous injection, the drug solution was
sterilized by filtration through a Millex-GV
0.22-µm-pore-size filter (Millipore Corporation, Bedford, Mass.).
Animal 608PR received 405 mg (0.75 mmol/kg of body weight) over 5 min, animal CH980 received 471 mg (0.76 mmol/kg) over 68 min,
and animal CH957 received 518 mg (0.69 mmol/kg) over 85 min.
This dose corresponds to 1,000 mg/m2.
Pediatric phase I trial.
The pediatric phase I trial and
pharmacokinetic study of KNI-272 were approved by the National Cancer
Institute's Institutional Review Board, and written informed consent
was obtained from the parent or legal guardian of each child.
(i) Study population.
Between November 1994 and November
1995, 21 children were enrolled in the pediatric phase I trial of
KNI-272. Pharmacokinetic studies were performed with 18 children (9 males and 9 females; median age, 9.4 years; age range, 2.7 to 16.8 years). Thirteen children had acquired HIV infection perinatally, and
the other five children in the pharmacokinetic studies acquired it from the transfusion of blood products or clotting factors. All children had
previously been treated with dideoxynucleosides, but none had received
a protease inhibitor. All children were in stable condition and free of
acute infections.
Patients were required to have a total leukocyte count of >1,500
cells/mm3 and a neutrophil count of >750
cells/mm3, a hemoglobin level of >8 g/dl, a platelet count
count of >75,000/mm3, a serum creatinine level of <2
mg/dl, and values for liver function tests <2.5 times the upper limit
of normal prior to study entry.
(ii) Study design, drug formulation, and drug
administration.
This 12-week pediatric phase I trial of KNI-272
was an open-label, dose-escalation study. The clinical results of this
trial will be reported separately. Pharmacokinetic sampling was
performed with separate cohorts of patients treated with one of four
dose levels: 100 mg/m2 per dose (n = 5),
200 mg/m2 per dose (n = 6), 330 mg/m2 per dose (n = 3), and 500 mg/m2 per dose (n = 5) (dose levels 1 to 4, respectively). For the two lower dose levels, a single intravenous dose
of KNI-272 was administered on the first day of treatment to evaluate
the pharmacokinetics of the drug. KNI-272 was subsequently administered
orally four times a day.
KNI-272 was manufactured by Pharmaceutical and Biotechnology Research
Laboratories, Nikko Kyodo Co. (Saitama, Japan), and
was distributed by
the Division of Cancer Treatment, National
Cancer Institute (Bethesda,
Md.). The intravenous formulation
was supplied in vials containing 50 mg of lyophilized powder with
3,000 mg of HPCD, a complexing agent
approved for investigational
use in humans. This powder was
reconstituted with 18 ml of 0.9%
sodium chloride injection, USP,
yielding a final concentration
of 2.5 mg of KNI-272 per ml. A single
dose of the drug (equivalent
to the oral dose) was infused over 1 h on the first day of treatment.
Oral KNI-272 was supplied as a 50-mg/ml liquid suspension which
included a suspension vehicle (Ora-Plus) and 25% cherry syrup.
Patients receiving the first two dose levels were given the full
oral
dose starting on day 2 of treatment. After one patient receiving
dose
level 2 experienced an acute, transient elevation of hepatic
transaminase levels, the single intravenous dose for the
pharmacokinetic
study was not administered to patients treated with
dose levels
3 and 4. The oral dose for dose levels 3 and 4 was
gradually escalated
to the target dose starting at 25% of the target
oral dose for
the first week, 50% for the second week, and 75% for
the third
week, with the full dose given starting on the fourth week.
This
schedule had previously been shown to reduce hepatic toxicity
in
the parallel National Cancer Institute trial with adults
(
11).
In one patient in the 200-mg/m
2 cohort who
had elevated enzyme levels by liver function tests
after receiving the
intravenous dose, drug administration was
interrupted and was then
reintroduced only at the 100-mg/m
2 dose level and oral
pharmacokinetics were determined only for
the 100-mg/m
2
dose level. Patients were instructed to take the suspension at
least
2 h after and 0.5 h before a meal because this has been
found
to improve absorption in adults.
(iii) Pharmacokinetic samples.
For the 1-h intravenous
infusion of KNI-272 for patients receiving the two lower dose levels,
blood samples (3 ml each) were drawn 0, 60, 75, 90, 120, 180, 240, and
360 min after the start of the infusion. The same patients were studied
after they received an oral dose on day 2 and after 12 weeks on the
protocol (samples were obtained at the same time points plus at 15 and
30 min). A second set of samples was obtained after the subjects had
been in the study for 12 weeks.
Sample analysis.
The KNI-272 concentrations in plasma and
CSF were measured by high-pressure liquid chromatography (HPLC). The
plasma samples and standards prepared in untreated plasma were
extracted with Bond-Elut C18 solid-phase extraction columns
(Varian, Harbor City, Calif.). The extraction columns were initially
primed with 3 ml of HPLC-grade methanol (Fisher Scientific Company,
Pittsburgh, Pa.) followed by 6 ml of deionized water. The samples or
standards (1 ml) were loaded onto the columns, the columns were then
washed with 2 ml of deionized water, and the drug was eluted from the column with two 0.5-ml aliquots of methanol. The eluant was evaporated to dryness under a stream of nitrogen, and the residue was
reconstituted in 200 µl of the mobile phase (see below). Prior to
injection onto the HPLC column the samples were clarified by
centrifugation through Ultrafree-MC 0.45-µm-pore-size filter units
(Millipore Corporation). The CSF samples were directly injected onto
the HPLC column.
Chromatographic analysis was performed on a Waters HPLC system
consisting of a WISP model 715 Ultra injector, a model 600E
solvent-delivery system, and a model 490 programmable multiwavelength
UV detector. The mobile phase consisted of 65% methanol, 35%
deionized
water, and 0.01% triethylamine (vol/vol/vol) at an isocratic
flow
rate of 1.4 ml/min through a Brownlee 5µm, OD-GU guard column
and a C
18 Steel Nova-PAK 4µm phenyl column (3.9 by 150 mm; Waters
Associates). The eluant was monitored at a wavelength of 230 nm.
Under these conditions, the retention time for KNI-272 was 8 min.
The standard curve was linear in the range investigated (0.1 to
10 µmol/liter), and recovery, verified by comparison with an aqueous
standard, was >90%.
Pharmacokinetic calculations.
A two-compartment open model
was fit to the plasma KNI-272 concentration-time data after
administration of an intravenous dose to nonhuman primates and
pediatric patients who were treated at the 200-mg/m2 dose
level by using MLAB nonlinear curve fitting software (Civilized Software, Bethesda, Md.) (17). The following differential
equations were used to describe the concentration in the central
compartment (Cc) and the amount of drug in the
peripheral (Xp) compartment at time
t:
where
k0 is the rate of drug infusion,
kel is the elimination rate constant,
kcp and
kpc are the rate
constants describing
the transfer between the central and peripheral
compartments,
and
Vc is the volume of the
central compartment. The data were
weighted by using the built-in MLAB
weighting function EWT, which
computes a weight vector from estimates
of reciprocal variance
values.
The fitted model parameters were then used to calculate clearance (CL;
CL =
Vc ·
kel) and the volume of distribution at steady
state {
VSS =
Vc
· [(
kpc +
kcp)/
kpc]}.
Half-lives were derived
from the rate constants as described previously
(
9). The area
under the concentration-time curve (AUC) in
CSF and after the
administration of an oral dose was calculated by the
linear trapezoidal
rule (
9). The fraction of drug
penetrating into the CSF was
derived from the ratio of the AUC in CSF
to the AUC in plasma.
The fraction of the oral dose absorbed
(
F) was estimated from
the ratio of the AUCs after
administration of oral and intravenous
doses of 200 mg/m
2.
| |
RESULTS |
Nonhuman primates.
The first animal (animal 608PR) received
KNI-272 intravenously over 5 min and experienced an acute adverse
reaction 3 min into drug administration manifested by facial erythema,
prolonged capillary refill, hypothermia, and a mild drop in blood
pressure which was treated by the administration of intravenous fluids. The animal's blood pressure and temperature normalized after 1 h,
but the animal remained lethargic and had intermittent chills for
several hours. No other infectious or metabolic etiology was identified. When the vehicle (HPCD) was injected alone as a 5-min bolus, no reaction occurred, and further infusions of KNI-272 were
administered over at least 1 h and were well tolerated.
The two-compartment model adequately described the disposition of
plasma KNI-272 concentrations. Table
1
lists the pharmacokinetic
parameters for the three animals. The
elimination of KNI-272 from
plasma was rapid, with a mean CL of 2.5 liters/kg/h (approximately
800 ml/min/m
2) and a mean
terminal half-life of 0.54 h. There was considerable
variability
in the disposition of KNI-272 in plasma, as evidenced
by the fivefold
range in CL and nearly fourfold range in terminal
half-life. The
penetration of KNI-272 into the CSF was extremely
limited. The level of
drug exposure in CSF (AUC) was only 1% of
that in plasma. The peak
concentrations of KNI-272 in CSF ranged
from 0.09 to 0.38 µM.
Pediatric phase I trial.
After the 1-h intravenous infusion of
KNI-272, the peak (end of infusion) concentration in plasma was 11 ± 8 µM at the 100-mg/m2 dose level and 19 ± 5 µM
at the 200-mg/m2 dose level. The concentration in
plasma declined rapidly to <0.1 µM by a median of 3 h after the
start of the infusion for the 100-mg/m2 dose level and
4 h for the 200-mg/m2 dose level. The
two-compartment pharmacokinetic model was fit to
the concentrations in plasma for five patients who received an
intravenous dose of 200 mg/m2. At the 100-mg/m2
dose level, there were too few measurable concentrations in plasma for
most patients for pharmacokinetic modeling. The pharmacokinetic parameters derived from administration of the intravenous dose are
listed in Table 2. KNI-272 was rapidly
eliminated in children. The mean CL was 276 ml/min/m2, and
the terminal half-life was 0.44 h. Drug distribution was also
limited. The mean Vc was 0.064 liter/kg, and the
mean VSS was 0.11 liter/kg.
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|
TABLE 2.
Pharmacokinetic parameters for KNI-272 administered
intravenously over 1 h and orally to children with
HIV infectiona
|
|
The oral absorption of KNI-272 administered with Ora-Plus in children
was limited and variable. In the five patients treated
with the
200-mg/m
2 dose level, the mean absolute bioavailability was
12% (range,
3.5 to 25%; Table
2). The median time to the peak
concentration
after the administration of the oral dose was 0.5 h
(range, 0.5
to 1.5 h). The maximum concentration of drug in plasma
and AUC
for patients treated with all four dose levels (Table
3) did
not appear to increase in
proportion to the increase in dose,
suggesting that the absorption of
KNI-272 was saturable in children.
There was a trend toward higher AUCs
after 12 weeks of continuous
oral therapy compared with the initial
measurement taken on either
day 2 (100- and 200-mg/m
2 dose
levels) or week 4 (330- and 500-mg/m
2 dose levels) of
treatment, but this difference was not statistically
significant
(
P = 0.065) for the 12 patients studied both initially
and at week 12.
Three patients receiving dose level 2 developed an increase in hepatic
transaminase levels that were between three and seven
times the upper
limit of normal. There was no apparent relationship
between the
pharmacokinetic parameters and the presence or severity
of
hepatotoxicity. No other dose-limiting toxicities were noted
during
this 12-week trial. There was no significant increase in
the percentage
or absolute numbers of CD4 cells and no significant
decrease in serum
p24 antigen or plasma HIV RNA levels.
| |
DISCUSSION |
Although the HIV protease inhibitor KNI-272 is active against HIV
in vitro, its pharmacokinetic profile in vivo may limit its efficacy in
treating patients with HIV disease. KNI-272 appeared to be rapidly
eliminated from nonhuman primates and HIV-infected children, and as a
result, the concentrations of KNI-272 in plasma are maintained above
the EC50 for less than half of the 6-h dosing interval
used. The bioavailability of KNI-272 was also limited and appeared to
be saturable over the dosage range studied in our phase I trial.
Therefore, simply increasing the oral dose of KNI-272 is not likely to
overcome the limited duration of exposure to concentrations exceeding
the EC50. The pharmacokinetic data suggest that a more
frequent dose administration schedule may be required to provide
continuous exposure to therapeutic concentrations of KNI-272.
KNI-272 is extensively protein bound (>98%) (12). In
preclinical studies, the EC50 increases from 0.004 µM
under standard in vitro conditions which include 15% fetal calf serum
to 0.1 µM in the presence of 80% fetal calf serum. This extensive
protein binding of KNI-272 indicates that higher concentrations will be required in vivo to achieve antiviral effects similar to those demonstrated in vitro. The extensive protein binding may also account
for its limited volume of distribution in our studies and contributes
to its limited ability to penetrate across the blood-CSF barrier.
Involvement of the central nervous system is an important and
often devastating aspect of HIV infection, especially in children
(4, 5). The limited penetration of KNI-272 into the CSF
suggests that KNI-272, used as a single agent, may not be useful for
treating HIV encephalopathy.
Four protease inhibitors (saquinavir, indinavir, ritonavir, and
nelfinavir) are currently approved for use in the treatment of
HIV-infected adults; ritonavir and nelfinavir are also approved for use
in children (8, 16, 19, 22, 23). Limited absorption and
difficulties in developing a liquid formulation have hampered the
initial development of this class of agents, particularly for use in
children. The rate of elimination of KNI-272 is more rapid than those
of other HIV protease inhibitors, such as ritonavir, which has a
terminal half-life of over 3 h (8). The
bioavailability of KNI-272 is higher than that of saquinavir (4%)
but lower than the relative bioavailability of indinavir sulfate (about
60%) (22, 24). Only limited data for pediatric subjects are
available for ritonavir and indinavir, but the pharmacokinetic
parameters are comparable in children and adults.
KNI-272 was rapidly absorbed in children. Peak concentrations were
achieved 30 to 60 min after administration of the oral dose in
children, and this is comparable to the time to the peak concentration
in adults (11). However, the extent of absorption appeared
to be lower in our group of pediatric patients (12%) than in adults
(30%) (11).
In summary, the pharmacokinetics of KNI-272 in children are
characterized by limited bioavailability, limited distribution (including poor penetration into the central nervous system), and rapid
elimination, suggesting that the role of KNI-272 in the treatment of
HIV-infected children may be limited.
| |
ACKNOWLEDGMENTS |
We thank the medical staff of the HIV & AIDS Malignancy Branch of
the National Cancer Institute for their help in caring for the
patients, Jewell Baker and Sydne Loy for data management support, and
Robert Yarchoan for critical review of the manuscript.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medicine, Hunnewell 302, Children's Hospital, 300 Longwood Ave.,
Boston, MA 02115. Phone: (617) 355-8733. Fax: (617) 738-7066. E-mail: mueller_b{at}a1.tch.harvard.edu.
| |
REFERENCES |
| 1.
|
Balis, F. M.,
P. A. Pizzo,
K. M. Butler,
M. E. Hawkins,
P. Brouwers,
R. N. Husson,
F. Jacobsen,
S. M. Blaney,
J. Gress,
P. Jarosinski, and D. G. Poplack.
1992.
Clinical pharmacology of 2',3'-dideoxyinosine in human immunodeficiency virus-infected children.
J. Infect. Dis.
165:99-104[Medline].
|
| 2.
|
Balis, F. M.,
P. A. Pizzo,
R. F. Murphy,
J. Eddy,
P. F. Jarosinski,
J. Falloon,
S. Broder, and D. G. Poplack.
1989.
The pharmacokinetics of zidovudine administered by continuous infusion in children.
Ann. Intern. Med.
110:279-285.
|
| 3.
|
Blaney, S. M.,
M. J. Daniel,
A. J. Harker,
K. Godwin, and F. M. Balis.
1995.
Pharmacokinetics of lamivudine and BCH-189 in plasma and cerebrospinal fluid of nonhuman primates.
Antimicrob. Agents Chemother.
39:2779-2782[Abstract/Free Full Text].
|
| 4.
|
Brouwers, P.,
A. Belman, and L. Epstein.
1994.
Central nervous system involvement: Manifestations, evaluation, and pathogenesis, p. 318-335.
In
P. A. Pizzo, and C. A. Wilfert (ed.), Pediatric AIDS. The challenge of HIV infection in infants, children, and adolescents. The Williams & Wilkins Co., Baltimore, Md.
|
| 5.
|
Brouwers, P.,
G. Tudor-Williams,
C. DeCarli,
H. A. Moss,
P. L. Wolters,
L. A. Civitello, and P. A. Pizzzo.
1995.
Relation between stage of disease and neurobehavioral measures in children with symptomatic HIV disease.
AIDS
9:713-720[Medline].
|
| 5a.
|
Carpenter, T. O.,
A. Gerloczy, and J. Pitha.
1995.
Safety of parenteral hydroxypropyl beta-cyclodextrin.
J. Pharm. Sci.
84:222-225[Medline].
|
| 6.
|
Chokekijchai, S.,
T. Shirasaka,
J. N. Weinstein, and H. Mitsuya.
1995.
In vitro anti-HIV-1 activity of HIV protease inhibitor KNI-272 in resting and activated cells: implications for its combined use with AZT or ddI.
Antivir. Res.
28:25-38[Medline].
|
| 7.
|
Collins, J. M.,
R. W. Klecker,
J. A. Kelley,
J. S. Roth,
C. L. McCully,
F. M. Balis, and D. G. Poplack.
1988.
Pyrimidine dideoxyribonucleosides: selectivity of penetration into cerebrospinal fluid.
J. Pharmacol. Exp. Ther.
245:466-470[Abstract/Free Full Text].
|
| 8.
|
Danner, S. A.,
A. Carr,
J. M. Leonard,
L. M. Lehman,
F. Gudiol,
J. Gonzales,
A. Raventos,
R. Rubio,
E. Bouza,
V. Pintado,
A. Gil Aguado,
J. G. de Lomas,
R. Delgado,
J. C. C. Borleffs,
A. Hsu,
J. M. Valdes,
C. A. B. Boucher,
D. A. Cooper, and The European-Australian Collaborative Ritonavir Study Group.
1995.
A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease.
N. Engl. J. Med.
333:1528-1533[Abstract/Free Full Text].
|
| 9.
|
Gibaldi, M., and D. Perrier.
1982.
Estimation of areas, p. 445-449.
In
J. Swarbrick (ed.), Pharmacokinetics. Marcel Dekker, Inc., New York, N.Y.
|
| 10.
|
Hawkins, M. E.,
H. Mitsuya,
C. M. McCully,
K. S. Godwin,
K. Murakami,
D. G. Poplack, and F. M. Balis.
1995.
Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys.
Antimicrob. Agents Chemother.
39:1259-1264[Abstract/Free Full Text].
|
| 11.
|
Humphrey, R. W.,
B.-Y. Nguyen,
K. M. Wyvill,
L. E. Shay,
J. Lietzau,
T. Ueno,
T. Fukasawa,
H. Hayashi,
H. Mitsuya, and R. Yarchoan.
1996.
A phase I trial of HIV protease inhibitor KNI-272 in patients with AIDS or symptomatic HIV infection.
In
Proceedings of the XIth International Conference on AIDS.
|
| 12.
|
Kageyama, S.,
B. D. Anderson,
B. L. Hoesterey,
H. Hayashi,
Y. Kiso,
K. P. Flora, and H. Mitsuya.
1994.
Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins.
Antimicrob. Agents Chemother.
38:1107-1111[Abstract/Free Full Text].
|
| 13.
|
Kageyama, S.,
Y. Mimoto,
Y. Murakawa,
M. Nomizu,
H. Ford, Jr.,
T. Shirasaka,
S. Gulnik,
J. Erickson,
K. Takada,
H. Hayashi,
S. Broder,
Y. Kiso, and H. Mitsuya.
1993.
In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine.
Antimicrob. Agents Chemother.
37:810-817[Abstract/Free Full Text].
|
| 14.
|
Kiriyama, A.,
K. Fujita,
S. Takemura,
H. Kuramoto,
Y. Kiso, and K. Takada.
1994.
Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor, KNI-272, in rats after intravenous administration.
Biopharm. Drug Dispos.
15:617-626[Medline].
|
| 15.
|
Kiriyama, A.,
T. Mimoto,
S. Kisanuki,
Y. Kiso, and K. Takada.
1993.
Comparison of a new orally potent tripeptide HIV-1 protease inhibitor (anti-AIDS drug) based on pharmacokinetic characteristics in rats after intravenous and intraduodenal administrations.
Biopharm. Drug Dispos.
14:697-707[Medline].
|
| 16.
|
Kitchen, V. S.,
C. Skinner,
K. Ariyoshi,
E. A. Lane,
I. B. Duncan,
J. Burckhardt,
H. U. Burger,
K. Bragman,
A. J. Pinching, and J. N. Weber.
1995.
Safety and activity of saquinavir in HIV infection.
Lancet
345:952-955[Medline].
|
| 17.
|
Knott, G. D.
1979.
MLAB a mathematical modeling tool.
Comput. Programs Biomed.
10:261-280[Medline].
|
| 18.
|
Kohl, N. E.,
E. A. Emini,
W. A. Schleif,
L. J. Davis,
J. C. Heimbach,
R. A. Dixon,
E. M. Scolnick, and I. S. Sigal.
1988.
Active human immunodeficiency virus protease is required for viral infectivity.
Proc. Natl. Acad. Sci. USA
85:4686-4690[Abstract/Free Full Text].
|
| 19.
|
Markowitz, M.,
M. Saag,
W. G. Powderly,
A. M. Hurley,
A. Hsu,
J. M. Valdes,
D. Henry,
F. Sattler,
A. La Marca,
J. M. Leonard, and D. D. Ho.
1995.
A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection.
N. Engl. J. Med.
333:1534-1539[Abstract/Free Full Text].
|
| 20.
|
McCully, C. L.,
F. M. Balis,
J. Bacher,
J. Phillips, and D. G. Poplack.
1990.
A rhesus monkey model for continuous infusion of drugs into cerebrospinal fluid.
Lab. Anim. Sci.
40:250-255.
|
| 21.
|
National Research Council.
1996.
Guide for the care and use of laboratory animals, p. 1-125.
National Academy Press, Washington, D.C.
|
| 22.
|
Noble, S., and D. Faulds.
1996.
Saquinavir. A review of its pharmacology and clinical potential in the management of HIV infection.
Drugs
52:93-112[Medline].
|
| 23.
|
Stein, D. S.,
D. G. Fish,
J. A. Bilello,
S. L. Preston,
G. L. Martineau, and G. L. Drusano.
1996.
A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir).
AIDS
10:485-492[Medline].
|
| 24.
|
Vacca, J. P.,
B. D. Dorsey,
W. A. Schleif,
R. B. Levin,
S. L. McDaniel,
P. L. Darke,
J. Zugay,
J. C. Quintero,
O. M. Blahy,
E. Roth,
V. V. Sardana,
A. J. Schlabach,
P. I. Graham,
J. H. Condra,
L. Gotlib,
M. K. Holloway,
J. Lin,
I.-W. Chen,
K. Vastag,
D. Ostovic,
P. S. Anderson,
E. A. Emini, and J. R. Huff.
1994.
L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor.
Proc. Natl. Acad. Sci. USA
91:4096-4100[Abstract/Free Full Text].
|
Antimicrobial Agents and Chemotherapy, July 1998, p. 1815-1818, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
