Abstracts Vol. 1 [International Conference on AIDS (11th: 1996: Vancouver, Canada)]

Tu.B.2323 - Tu.B.2328

Tuesday July 9, 1996

renal function.The duration of therapy ranged between 3 and 40 days at the time of blood
sampling and the mean dose was 0,7 g t.i.d.(range 0.5- I).
Results: Residual serum levels were < 0,2mg/ml (cut-off value) in six patients. Only two
patients had relatively high concentration of paromomycin, one of these two patients had
renal failure at the time of blood sampling.
Conclusions: Unlike previous studies, these results suggest that relatively high serum levels
of paromomycin can be reached in patients with AIDS and could impair renal function in
long-term oral therapy Alterations of intestinal mucosa observed during cytomegalovirus or
cryptosporidium infection could increase the absorption of paromomycin. Further pharmacokinetic studies are warranted to confirm our data.
Gilquin J., Unite d'Immunologie, HOpital Broussais 96, rue Didot - 75674 Paris Cedex 14 -
France Telephone: (33-1I) 43 95 81 50 - Fax: (33-1I) 43 95 95 24
Tu.B.2323
EFFECTS OF FOOD OR ANTACID ON THE BIOAVAILABILITY OF NEVIRAPINE 200
MG TABLETS
Lamson M, Cort S, Macy H, Love J, Korpalski D, Pay J, Keirns J. Boehringer Ingelheim
Pharmaceuticals, Inc., Ridgefield, CT
Nevirapine, a non-nucleoside reverse transcriptase inhibitor of the human immunodeficiency virus (HIV- I), has been developed for treatment of the HIV- I infection in humans. A randomized, three-treatment, four period crossover study was conducted to determine the
effects of food (high-fat breakfast) or antacid (Maalox~) on the bioavailability of nevirapine
200 mg tablets.Twenty-four adult volunteers (I2 male, I12 female) were assigned to one of
six treatment groups, which differed with respect to sequence, and received the following
treatments: nevirapine 200 mg after an overnight fast (control), high-fat breakfast (eggs,
bacon, hash browns, buttered toast, orange juice and milk) + nevirapine 200 mg, and
antacid (Maalox~ 30 mLs) + nevirapine 200 mg. Nevirapine was administered with 200
mLs of water. Serial blood sampling followed dosing; plasma nevirapine concenti ations were
determined using a validated HPLC assay with a limit of quantitation of 25 ng/mL. A general
linear models procedure was performed to test for treatment differences in nevirapine
bioavailabilityThe rate of nevirapine absorption was significantly decreased by administration
with food or antacid as evidenced by a delay in time-to-peak plasma nevirapine concentrations (Tmax, 4.4 hours fasted, 6.3 hours fed, 8.4 hours antacid), reduction in the peak concentration (Cmax, 2.0 pg/ml fasted, I1.9 pg/mL fed, I1.7 pg/mL antacid) and increase in the
first-order absorption half-life (TI/2abs, 0.5 hours fasted, I.3 hours fed, I.I hours antacid).
However, there was no statistically significant effect on the nevirapine plasma concentration
profile (AUC[infinity]) by food (p=0.20 I) or antacid (p=0.148) compared to fasted. Overall,
the results indicate that nevirapine can be administered with or without food or antacid
without altering nevirapine bioavailability.
Susannah Cort, M.D. Boehringer Ingelheim, 900 Ridgebury Road (203) 791I-6063 Ridgefield,
CT 06877
Tu.B.2324
DEVELOPMENT OF A NONLINEAR POPULATION PHARMACOKINETIC (PPK)
MODEL FOR DELAVIRDINE MESYLATE (DLV) IN HIV-I PATIENTS
Cox, Steven R., Phillips, L.*, Grasela,TH.*. Pharmacia and Upjohn, Inc., Kalamazoo, MI, USA;
and *Pharmaceutical Outcomes Research, Inc., Williamsville, NY USA.
Objective: To develop a PPK model which can be used to analyze DLV concentration
(conc) data from Phase III studies.
Methods: Plasma DLV cone data were pooled from 7 multiple-dose PK studies which
included total daily DLV doses of 60-1200 mg and extensive sampling for DLV cone after at
least two doses.The database contained 3996 cone records from 128 patients, and DLV
cone ranged from 0.06- I OOpM (median 8pM). Modeling was performed with NONMEM.
Results: Single and multiple-dose PK of DLV were best described by a I-compartment
model with I st-order absorption, parallel I st-order and Michaelis-Menten clearance, and a
nonlinear bioavailability function.To account for a DLV-induced inhibition of metabolism,Vm
was allowed to change after 24 hr Residual and inter-individual variability were described by
proportional error and combination additive+proportional error models, respectivelyThe
median prediction errors (predicted-measured conc) were 0.6pM and -0.9pM for measured cone of 0-5pM and >5pM, respectively Residual variability was <32% CV
Conclusion: This PPK model adequately describes the pooled DLV data and will be further
evaluated in analyses of Phase Ill data.

Results: Ratios of NVP in plasma and tissues are shownf in Table I.Total radioactivity (NVP
and/or its metabolites) was uniformly distributed throughout the body In pregnant rats,
NVP and its rmetabolites crossed the placental barrier and were uniformly distributed
throughout the fetuses.

Plasma:brain
Plasma:cerebrc
Plasma:thymus
Plasma:lymph
Plasma:bone rr

Table I: Ratios of Nevirapine
Monkey
1:1.1
I:t.I
ospinal fluid 1:0.39
1:0.88
dni I109(1

Rat
1:0.99
1:1.2
1:1.4
1:0.60

narrowe
narrow:.60
1:0.60

Conclusions: NVP freely enters the brain where it may inhibit replication of HIV- I and thus
be of potential therapeutic value in the treatment of HIV- I related dementia. Evidence in
animals supports the contention that inhibitory antiviral concentrations of NVP should be
achieved in all areas of the body in which a viral burden may be present.
Peter M. Grob, Ph.D., Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd.,
Ridgefield, CT USA: Phone: [phone] I 26; Fax: (203) 79 I -6468
Tu.B.2326
NEVIRAPINE,A NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR: METABOLISM IN MAN, MOUSE, RAT, DOG, CYNOMOLGUS MONKEY AND CHIMPANZEE
Riska P Erickson D, Joseph D, Dinallo R, Hattox S. Boehringer Ingelheim Pharmaceuticals.,
Inc., Ridgefield, CT USA
Objective: To elucidate the biotransformation pathways and enzymes involved in the
metabolism of nevirapine (NVP) in humans and determine the consistency of metabolic

2II t t LUroYe
2-OHLNVP $-OH-NVP

pathways across species.
Methods: Eight male volunteers received tablets
containing 200 mg NVP qd for 2 weeks, followed
by 200 mg tablets b.i.d. for an additional 2 weeks.
Twenty-four hr after the last dose, a single dose
of 14C-NVP in solution was administered and
blood, plasma, urine and feces were collected up
to 4 days. Male and female animals were administered 20 mg/kg 14C-NVP in suspension and plasma (rat and dog only). urine and feces were collected. NVP metabolites were separated by
HPLC/diode array/radioactivity detection and
their structures were identified by LC/MS/MS. In

vitro metabolism was conducted using human
liver microsomes and cDNA-expressed human cytochromes P450.
Results: Oxidative metabolism to 2, 3, and I 2-hydroxyNVP was followed by phase II
metabolism to form the glucuronide conjugates (see Figure). Minor metabolites were 8 -hydroxyNVP and 4-carboxyNVP. Metabolism in animals was similar to that in humans,
except for the female rat that formed an additional 3 unknown metabolites. Less than 3%
was excreted in man as unchanged drug.
Conclusions: NVP was cleared from the systemic circulation mainly v a hepatic metabolism
by cytochrome(s) of the CYP 3A subfamilyThe toxicology species (rat and dog) were good
models for human.
Susan Ellen Hattox, Ph.D., Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd,
Ridgefield, CT, USA: Phone: [phone]; Fax: (203) 79I -6003
Tu.B.2327
ACIDIFICATION STRATEGIES IN HIV + SUBJECTS WITH GASTRIC HYPOACIDITY
Shelton, Mark I*, Adams Jy, Hewitt R*, Cox 5**, Chambers J**, Freimuth W**, Carberry P**,
Morse G*. *SUNY Buffalo, Buffalo, NY USA; **Pharmacia & Upjohn, Inc., Kalamazoo, MI. USA
Objective: To compare methods for gastric acidification in HIV + subjects with spontaneous
gastric hypoacidity (GH) in terms of pH effects and impact on pharmacokinetics (PK) of
delavirdine mesylate (DLV), a non-nucleoside reverse transcriptase inhibitor of HIV- I.
Methods: Administration of DLV with orange juice (OJ) and glutamic acid (GA) were each
compared to water in two separate PK studies. HIV + subjects (n=6) with GH (fasting gastric pH >3) who participated in both studies were included in a comparison of the acidification regimens across the two studies. In combination with nucleosides (ddl excluded), DLV
400 mgTID was compared given with OJ versus water (H20), followed by the same regimen given with GA (4x340 mg capsules) versus H20. Acidification treatments (Treat) were
separated by 0.3- I years. DLV was determined by HPLC and analyzed by noncompartmental methods. Minimum gastric pH (min pH) was determined during each PK study day using
a consumable, radiotelemetric device.
Results: Mean ~ SD PK parameters are listed below:
Study Treat Cmax(M) AUC(iM - h) min pH Treat Cmax(pM) AUC(pM - h) min pH

Parameter
Ka (I/hr)
Km (pMoles)
Vm (pMoles/hr)
Vrn (pMoles/hr)
Ke (I/hr)
Vd (L)

Population Mean
Estimate %SEM
2.6 17
20 18
30 8
21 9
0.049 10
65 6

Inter-individual
Estimate
157
38
43
36

Variability (%CV)
%SEM
32
30
30
27

I st 24 hr
>24 hr

Steven R. Cox, Ph. D. Pharmacia and Upjohn, Inc. 30 I Henrietta Kalamazoo, MI 49007 Tel:
[phone] Fax: [phone]
Tu.B.2325
NEVIRAPINE,A NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR, FREELY
ENTERS THE BRAIN AND CROSSES THE PLACENTAL BARRIER
Silverstein H, Riska P Johnstone JN, Richter I*, Norris 5, Hattox 5, Grob P. Boehringer
Ingelheim Pharmaceuticals., Inc., Ridgefield, CT USA and *Boehringer Ingelheim GmnbH, D552 I 6 Ingelheim/Rhein.
Objective: To determine the distribution of nevirapine (NVP), the extent to which it permeates the blood-brain barrier to enter the central nervous system (CNS) and its passage
through the placental barrier and distribution in the fetus.
Methods: Male and female rats and cynomolgus monkeys were administered 20 mg/kg
NVP in suspension orally Plasma, brain, thymus, lymph node and bone marrow were collected at 2 hr post-dose and analyzed for NVP by HPLC. Male and pregnant female rats
were administered I14C-NVR and tissue distribution of radioactivity was determined by
combustion and/or autoradlography

I H20 8.8~2.7
II H20 9.6~4.2
p H2Ov.H20 0.735

47~19 3.9+0.97 OJ 13~5.2 68~33 1.9~1.4
44~+24 3.4~1.2 GA 16+~8.4 73+~44 1.6~0.49
0.612 0. 180 OJv.GA 0.499 0.866 0.670

Conclusions: Both OJ and GA reduced pH and increased DLV absorption relative to
H20. Cross study comparisons indicate similar effects with each TREATThus, OJ may
acidify gastric contents as well as GA, but is a more convenient for chronic medication
regimens. Due to the small sample size, only large differences between the acidification
regimens can be excluded.
Mark J. Shelton, 245 Cooke Hall, Buffalo, NY USA Telephone: [phone]!3 Fax: 7 I 6-898-3707
Tu.B.2328
CIPROFLOXACIN PHARMACOKINETICS IN SEVERELY ILL PATIENTS
F. Maggiolo 1,W Bianchi2, M.Tellarini2, H. Sta3 3, j. Kuhlmann 3, F. Suter'. General Hospital,
Busto Arsizio, Italy1;Bayer SpA, Milano, Italy; Bayer AG, Wuppertal, Germany3.
Objective: To determine the pharmacokinetic behaviour of intravenous ciprofloxacin in
severely ill AIDS patients.