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

Track B: Clinical Science

Mo.B. 193 - Mo.B.l 198

Mo.B.1 193
DRUG REACTIONS TO CO-TRIMOXAZOLE IN HIV INFECTION POSSIBLY NOT
DUE TO HYDROXYLAMINES
PPKoopmans, A van derVen,TVree, JWM van der Meer. Department of Medicine and
Department of Clin Pharmacy University Hospital St.Radboud Nijmegen,The Netherlands.
Objective: To test the hypothesis that the increased incidence of drug reactions to cotrimoxazole (CTR) in HIV infection is due to the metabolite of sulphamethoxazole (SMZ),
especially the hydroxylamine (HYD) of SMZ
Methods: Co-soltnim(CSM) is a combination of sulfametrole(SMT) and trimethoprim.The
phirmacokinetics of SMT is similar to that of SMZ, but the metabolism differs: acetylation is
less, in human liver microsomes we found less hydroxylation, and after CSM we could not
detect HYD in the urine of healthy volunteers.We rechallenged 8 HIV seropositive
patients, with a history of rash or fever on CTR with CSM.Three patients had AIDS and a
PCP 4 with CD4 counts< 200/mm3 were on pentamidine aerosole.
Results: All but one of the re-challenged patients had a recurrence of rash. One patient had
an immediate anaphylactoid reaction, the other experienced rash or fever after treatment
for 3- 10 days with a dose of 960 mg o.i.d.One patient had an increase of liver enzymes. All
symptoms disappeared after discontinuation of CSM.
Conclusion: This rechallenge experiment cast doubt on the hypothesis, that HYD cause the
drug reactions of sulphonamides and suggests that either other metabolites, the parent
compound, or immunological factors are responsible.
PPKoopmans, Department of General Internal Medicine, University Hospital St.Radboud
PO Box 9101, 6500 HB Nijmegen, Netherlands
Mo.B.I 194
DRUG INTERACTIONS WITH d4T PHOSPHORYLATION IN VITRO
Back, David, Haworth S, Hoggard P*, Khoo S*, Barry M*. University of Liverpool,
Liverpool, UK*; Bristol-Myers Squibb, Princeton, NJ, USA**
Objective: The dideoxynucleoside analogue d4T (2,3'-dideoxy-2',3'-didehydrothymidine;
Zerit~), in common with other nucleoside analogue reverse transcriptase inhibitors,
requires intracellular phosphorylation to the active triphosphate anabolite for inhibition of
HIV replication. In AIDS patients d4T will be co-administered with many other drugs and it
is essential to know if there are drugs which interfere with the phosphorylation process.
Therefore the aim of the present study was to evaluate drug interactions with d4T at the
intracellular phosphorylation level.
Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from non-HIV-infected blood and were stimulated by pre-incubation with the mitogen phytohemagglutinin
(PHA, I Opg/mL for 72 h. Stimulated PBMCs (3 x 106 cells/plate) were then incubated with
H d4T (0.65pCi, 3 pM) and other drugs (0.3-300 pM) for 24 h.The other drugs investigated were: i) antivirals: acyclovic ddl, foscarnet, ganciclovir, lobucavir, ribavirin, sorivudine, 3TC,
zidovudine and ii) other drugs commonly used in HIV infected patients: dapsone, doxorubicin, fluconazole, fluoxetine, ranitidine, rifampicin, sulfamethoxazole, trimethoprim. Cells
were extracted overnight with 60% methanol prior to analysis by radiometric HPLC.The
mono. di- and triphosphate anabolites were identified by comparison with retention times
of authentic standards. Cell incubations were performed in triplicate with at least 5 separate
blood preparations. Cell viability was assessed by the method of neutral red uptake.
Results: ZDV had a significant effect on d4T phosphorylation at a molar ratio of 0. I (4 1%
decrease; p<0.OI ANOVA), 1.0 (67% decrease; p<0.00I) and 10 (83% decrease; p<0.001)
without evidence of cell toxicity Both ZDV and d4T are thymidine analogues. In contrast,
the cytidine analogue 3TC and the inosine analogue ddl had no effect on d4T phosphorylation. Significant inhibition of phosphorylation was evident in incubations with ribavirin and
thymidine at 30 pM and additionally with fluconazole, fluoxetine, rifampicin, 3TC and sulfamethoxazole at 300 pM. However, there was clear evidence of cell toxicity for fluconazole, fluoxetine, rifampicin and sulfamethoxazole at the highest concentration. Doxorubicin
was the only drug other than ZDV to give significant inhibition of phosphorylation at a concentration of 3 pM (52% inhibition; p<0.01 ) but since doxorubicin is cytotoxic at this concentration it is difficult to separate the effect on phosphorylation from overall cell toxicity.
Conclusions: This study has shown that ZDV interferes with d4T phosphorylation in vitro;
this may have implications for combination therapy in patients.The only other drugs studied
which may interfere with d4T phosphorylation at clinically relevant concentrations are ribavirin and doxorubicin.
Prof D. J. Back, Dept of Pharmacology and Therapeutics, University of Liverpool, PO Box
147, Liverpool, L69 3BX, UK;Tel: 44 15 I 794 5547; Fax: 44 151 I 794 5540 Email:
[email protected]
Mo.B.I 195
A CASE OF ISONIAZID (INH) INDUCED OPTIC NEUROPATHY IN AN
ASYMPTOMATIC HIV INFECTED WOMAN AND REVIEW OF THE LITERATURE
Martin Susan G*, Weidle PJ*, Rismondo V**, Bever S**, Wheeler, DA*. *University of
Maryland Medical Center; *"Greater Baltimore Medical Center, Baltimore, Maryland.
Issues: INH is frequently prescribed for HIV infected individuals with a reactive tuberculin
skin test (+PPD) or with active tuberculosis. Optic neuropathy is a rare complication associated with INH.
Project: We report the irst case of INH induced optic neuropathy in an HIV infected adult.
Results: A 35-yearold woman with asymptomatic HIV infection and a CD4 cell count of
804 cells/rm3, who was well nourished, had no history of liver disease, and used no medications or ethanol, was begun on INH 300 mg/day and pyridoxine 50 mg/day for a +PPD.
Two weeks after initiation of INH, she complained of bilateral numbness in her arms and
legs. Medications were continued and four weeks later she noted a sudden loss of visual
acuity in the left eye and a bitemporal hemianopia. INH was discontinued. Ophthalmologic
and neurologic consultants agreed on a diagnosis of optic neuropathy Chemistry and hematology studies were normal. A cranial MRI revealed no pathologyThe CSF contained I
WBC, 40 RBC/mm3, protein of 49, and glucose of 6 I mg/dL. CSF cryptococcal antigen, teaoplasma antibody, VDRL, myelin basic protein, oligoclonal bands, and cytology were negative.
No progression or irmprovement was seen after I8 months.
SeveNteen cases of INh-assocrated visual loss have been described in HIV negative persons,
I men, 6 women: age 7-7 I ).Two were on NH alone, 6 were on ethambutol as a part
of the treitment regimen. Five cases were associated with peripheral neuropathy Onset of

visual loss was within 6 months in 12/17 cases (range 9 days-15 months).Visual improvement was noted in I I cases, in which INH was discontinued in 10. Pyridoxine was added or
increased in 7 cases, and prednisone was added in 3.
Lessons Learned: Although rare, clinicians treating HIV need to be aware of the ocular
toxicity of INH.
Susan G. Martin, N.P [phone], 22 South Greene Street, Box 174, Baltimore,
Maryland 21201
Mo.B.I 196
THE EFFECT OF FLUCONAZOLE ON THE CLINICAL PHARMACOKINETICS OF
METHADONE
Cobb M*, Desai J, Brown, Lawrence S.*, Zannikos PTrapnell C, Rainey P *Addiction
Research &Treatment Corporation, Brooklyn, NY and the Terry Beirn Community
Programs for Clinical Research on AIDS (CPCRA), NIAID, NIH, Washington, DC
Objective: To evaluate the possibility of a drug-drug interaction between fluconazole (FLU)
and methadone (METH) in METH-maintained patients.
Methods:Twenty-five METH-maintained patients were enrolled into the studyThe study
was a randomized, double-blinded, placebo-controlled, pharmacokinetic and safety study in
which patients received either oral FLU 200 mg/day (n= 13) or placebo (n- 12) for 14 days
with their individual daily METH dosage. Serum and urine specimens were collected at
intervals over a 24-hour period at baseline and after 14 days. At baseline, mid-study and
after 14 days, patients were assessed for signs and symptoms of narcotic withdrawal and
overdose.
Results: There was a 30% increase in METH concentration (area under the concentration
versus time curve [AUC]) observed in patients receiving FLU (p=0.0008). Consistent with
the AUC increase, CI0 of METH was significantly reduced by 26% in the FLU group
(p0.0007).The Cmin, Cmax and Css of METH were all increased by 41% (p=0.0076),
23% (p=0.0023) and 30% (p=0.0008), respectively, in patients receiving FLU.There was no
significant difference in METH Tmax, CIr or urine pH after 14 days of FLU therapy. Based on
the symptomatologic data, concomitant administration of FLU and METH did not precipitate signs or symptoms of narcotic withdrawal and overdose. On a scale of none (0), mild
(+ I), moderate (+2) and severe (+3), the few symptoms reported were described as mild
and are not pathognomonic of narcotic withdrawal or overdose. No modifications of
METH dosage were warranted during the study
Conclusion: Although significant changes in METH pharmacokinetics were observed after
concurrent administration with FLU, the combination did not appear to produce any
changes of clinical significance in METH-maintained patients.
Lawrence S. Brown, Jr, MD, MPH Addiction Research and Treatment Corporation, Brooklyn,
NY 11201 Telephone: [phone]; Fax: [phone]
Mo.B.I 197
EFFECT OF RITONAVIR ON THE PHARMACOKINETICS OF TRIMETHOPRIM /
SULFAMETHOXAZOLE
Bertz RJ, Cao G, Cavanaugh JH, Hsu A, Granneman G Richard, Leonard JM. Abbott
Laboratories, Abbott Park, IL
Objective: To evaluate the pharmacokinetic effects of concomitant administration of multiple doses of the HIV-I protease inhibitor ritonavir on single doses of the antiinfective combination of trimethoprim and sulfamethoxazole (TMP/SMX).
Methods: This was an open label study during which each of 15 healthy male and female
volunteers received a single dose of I 60 mg/800 mg ofTMP/SMX (BactrimTM DS) on
Study Days I and I 3. Ritonavir was administered to each subject on Days 3 through I 4 as
follows: 300 mg q 12h (Day 3), 400 mg q 12h (Day 4) and 500 mg q 12h (Days 5-14). SMX,
N-acetyl SMX and TMP pharmacokinetics were determined for a 48-h period after each
single dose ofTMP/SMX; concentrations were measured by HPLC with UV detection.The
difference in pharmacokinetic parameters f-rom the absence (Day I) to the presence (Day
13) of ritonavir were evaluated using the paired t-test onr, if nonnormality was evident, the
nonparametric signed-rank test was used.
Results: Compared to administration in the absence of ritonavir, the mean AUC of SMX
decreased by 19.8% (p<0.001) and harmonic mean half-life decreased by 1.6 h (7.3 vs. 8.9
h, p<0.001 ) with no significant change in mean Cmax (40.3 vs. 45.0 pg/mL, p=0.135) during
ritonavir administration. In addition, the AUC of N-acetyl SMX was decreased by 10.4%
(p=0.025). In contrast, the mean AUC ofTMP was increased by 19.9% (p=0.04 I), with a
corresponding increase of 2 h in the harmonic mean half-life (I 1.8 vs. 9.8 h, p=0.022), without a significant change in mean Cmax (I.28 vs. 1.30 pg/mL, p=0.524).
Conclusions: The minor changes in TMP/SMX pharmacokinetics suggest that ritonavir
enhanced the clearance of SMX, possibly by induction of N-glucuronidation and decreased
the clearance ofTMP probably by inhibiting cytochrome P450 mediated biotransformation.
Given the limited magnitude of the opposing changes in TMP and SMX AUC and the wide
safety margin of this synergistic combination, the noted pharmacokinetic changes are likely
not clinically relevant.
G.R. Granneman, D4PK / API 3A, 100 Abbott Park Road, Abbott Park, IL 60064-3500
Phone: [phone] Fax: [phone] email: [email protected]
Mo.B.I 198
EFFECT OF RITONAVIR ON THE PHARMACOKINETICS OF ETHINYL ESTRADIOL
IN HEALTHY FEMALE VOLUNTEERS
Ouellet, Daniele, Hsu A, Qian J, Cavanaugh J, Leonard J, Granneman GR. Abbott
Laboratories, Abbott Park, IL, U.S.A.
Objective: To investigate the effects of the HIV- I protease inhibitor ritonavir on the pharmacokinetics of ethinyl estradiol (EE).
Methods: This was an open-label, single-center study in 23 healthy female volunteers.
Subjects received the first dose oral contraceptive (OC) containing S0 pg of FE and I
mg of ethynodiol diacetate on Day I and a second dose on Day 29 with concomitant
ritonavi. Each subject received I 6 days of ritonavir from Day I 5 through Day 30, with 300
mg q I2h on Day 15, 400 mg q I2h on Day Is6, and 500 mg q I2h thereafter Blood samples
for determination of serum EE by GC/mass spectrometry were collected for 48 h after
each OC dose. Blood samples for plasma ritonavir were collected at baseline (Day I an 0
h), and on Day 29, at 0 and 4 h post-dose and assayed using a HPLC-UV assay.,,o
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