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

Mo.B.l 199 - Mo.B.1204

Monday, July 8, 1996

Results: Admnistration of the OC with ritonavir resulted n statistically significant decreases
in EE mean Cr ax (- 32%) and mean AUC ( 4!%), and a statistically significant increase in
the mean terminal elimination rate constant (+31 %).The ratios of means (95% confidence
intervals) for Cmax and AUC were 0.682 (0.6 12-0.758) and 0.595 (0.506 0.694), respectively The harmonic ean term ilf hlife decreased from 7 h to I 3 h during concomitant ritonavr: No statistically signficant change was noted in Trmax. Every subject had
detectable rilonavir concentrations after two weeks of dosing (Day 29), with mean steadystate concentrations of 6.5 and I 3.4 pg/mnL t 0 and 4 h post dose, respectivelyThe
changes in E pharmacoknetis are consistent with an increase in clearance from enzymatic
induction of lucurnidrdtiori arnd/or iytochrome P4150 hydroxylation.A decrease in absorption as the sole cause for the interaction is unlikely since an increase in EE terminal elimination rate constant was observed with concomitant ritonavir.
Conclusion: Considernng the extent of decrease in EE concentrations, use of alternate contraceptive measures should be considered when ntonavir s being administered.
D. Ouellet, D4PK/AP I 3A, 100 Abbott Park Rd., Abbott Park, IL 60064 3500. USA.
Telephone: [phone], Fax: [phone], email: [email protected]
Mo.B. 1199
ASSESSMENT OF MULTIPLE DOSES OF RITONAVIR ON THE PHARMACOKINETICS
OF RIFABUTIN
Cato, Allen, Cavanaugh JH, Shi H, Hsu A, Grannerman GR., Leonard J. Abbott Laboratories,
Abbott Park, IL
The pharmacokinetics of the antimycobacteriil rifiabutin (Mycobutin@) and its active
metabolite 25-0 desacetyl-rifaibutin were assessed with concurr ent administration of the
HIV-I protease nhibtortr itonair or placebo in 24 healthy males and females in a doubleblind, parallel group study After a 14-day ead-in period of dosing with 150 mg rifabutin
QD, subjects were dosed for an additional 1I0 days with either a combination of 150 mg
rfabutin QD and placebo, or a combination of 150 mg rifabutin QD and the following
escalating doses of ritonavir twice daily: 300 mg (Study Day 15).400 mg (Study Day 16)
and 500 mg (Study Days I 7-24). Rifabutin pharmacokinetics were determined on Study
Days 14 and 24. Rifabutin pharmacokinetics were altered substantially by the addition of
ritonavir. The ratio of the adjusted means of the two groups from analysis of covariance
indicate that concurrent ritonavir dosing increases the means for rifaibutin Cmin, Cmnax, and
AUC0 24 by approximately 6, 2.5, and 4-fold, respectively and increases the means for 25 -O-desacetyl rifabutin Cmin, Cmax, and AUCO-24 by approximately 200-, 16, and 35-fold,
respectively.I The sum of the adjusted mean AUCO-24 of rifabutin and 25-0-desacetylrifabutin increased nearly 7 -fold with the combination compared to administration of
rifabutin alone.These substantial changes in rifabutin and 25-0 -desacetyl rifaibutin pharmacokinetics suggest that ritonavir inhibited the metabolism of both rifabutin and 25-0 -desacetyl-nfabutin, and may have enhanced the bioavailability of nifabutin by decreasing
intestinal wall and hepatic first pass metabolism. Because of the substantial increases in
rifabutin and 25-O -desacetyl-rifabutin concentrations and the greater incidence of adverse
events with the combination of rifiabutin and ritonavir, an alternative to rifabutin for antimycobacterial therapy (., clarithromrycin) is recommended during ritonavir therapy
A Cato Abbott Labor Stories, 100 Abbott Park Road, Abbott Park, IL 60064
Telephone: [phone] Fax: [phone] email: Allen.E.Cato(@dAbbott.com
Mo.B. 1200
ASSESSMENT OF MULTIPLE DOSES OF RITONAVIR ON THE PHARMACOKINETICS
OF THEOPHYLLINE
Hsu Ann, tiranneman G R,Witt 0, iava naugh JH, Leonard J. Abbott Laboratories, Abbott
Park, IL
Objective: To assess t he effect ofr itonavir (an Hr IV protease inhibitor) coadministration on
the steady-state ph armacokinetics of theophylline.
Study Design:Twenty seven subjects (3 female) completed the 5-day theophylline lead-in
period (3 mng/kg q8h). On Day 6, subjects were randomized in a 2:3 ratio to receive Reg. A
(theophylline+ritonavir placebo) or Reg. B (theophylline+ritonavir). Ritonavir was given q12h
in escalating doses: 300 my on Day 6,400 mg on Day 7 and 500 mg during Days 8- 15.
Results: Relative to Reg.A, coadministration of nrtonavir with theophylline for 10 days
decreased (p<0.05) the steady-state (55) theophylline Cmax, AUC, and Cmin by 32%, 43%,
and 57%, respectively with individuals with the highest initial clearances of theophylline
showing the smallest effects.The overall also decreased from 8.4 h at baseline to 3.6 h
after coadministration with ritonavir for I0 days. A smaller extent of decrease in SS theophylline Cmax (1 3%), AUC (I 6%), and Cmin (27%) was observed on the fourth day of
coadministration with ntonavir Ritonavr had little or no effect on the theophylline trough
concentration after coadministration for 2 days (Days 7 and 8). However, ritonavir stat signify decreased theophylline trough concentrations during Days 9-15 in a time-dependent
fashion.The effect of ritonavr on the theophylline trough concentrations appeared to stabilize after coadministration for 6 days (Day 12).These time- dependent effects were probably
due to increased CYP IA2 activity after multiple dosing with ritonavit.There was little or no
evidence of pronounced effect on theophyline trough concentrations during the first few
days of codmInistrati on with itonavir when the induction was minimal.This suggests riton
avir is a very weak CYP IA2 inhib tor Since theophyline has a relatively narrow therapeutic
range. dosage adjustment is probably necessary when ritonavir is coadministered.
Ann H-Isu, DPK/AP 13A, I00 Abbott P irk Road, Abbott Park, IL 60064-3500
Phone: [phone] Fax: [phone] email: [email protected]
Mo.B. 120 I
EFFECT OF RITONAVIR ON THE PHARMACOKINETICS OF DESIPRAMINE
Bertz Richard J, Ca C, Caivnaugh JH, Hsu A, Granneman GR, Leonard JM. Abbot
I abor ator es, Abbett Pairk, l
Objective:Tr eval cte the prtential for oncurrent doskng of the HIV- protease nhibitor
rtonivr tC Iave i dirny yin(DMIt efet o the phirmacokinetics of the ticyclit ant dvpiessant (T A) On pirtne UMI.

Methods: This was an open label study during which each of 14 healthy male and female
volunteers received a single dose of 100 mg DMI (Norpramin~) on Study Days I and II
Ritonavir was administered on Days 8-19 as follows: 300 mg qi 2h (Day 8), 400 mg q12h
(Day 9) and 500 mg q 12h (Days 10- 19). DMI and major nmetabo lite 2-OH DMI pharmacok netics were determined for a 96-h per od after the Day I dose (alone) and a 2 16h penod after the Day I I dose (during ntonavir dosig); plasma concentrations were,asured
by LC/MS/MS. Ritonavir plasma concentrations were meas red by HPL C. CYP2D6 pheno
type and genotype were determined for each subject. Changes in pharmacokineticic p, me- n
ters were evaluated by the paired t test.
Results:The mean AUC of DMI increased 2.45-fold (p<-0.001), harmon icean hail Ife
increased nearly 2 -fold (34.8 vs. 17.6 h, p<0.001) and mean Cmax increased by 22.% (39.2
vs.32. I ng/mL, p<0.001) despite a longerTmax (I 0.4 vs. 67 h, p=0.002) dunring ntonav:
administration.The 2-OH metabolte to parent ratio mean decreased by 67% (0.28 vs. 0.84,
p<0.001) and 2-OH DMI mean Cmax decreased by 67% 8.9 vs.26.9 ng/nL, p0.001). All
subjects were phenotyped as CYP2D6 extensive metabolizers (EMs). Seven subjects were
heterozygous for the deactivating B mutation (8/wt) and 7 were wt/wt, B /wt genotype had a
higher DMI AUC mean (73.7%, p-0.020) on Day I than wt/w. No significant relationship
was noted between ritonavir AUC and the increase in DMI AUC, but the higher the Day I
DMI clearance (lower AUC),the greater the increase in DII AUC on Day I 0 (r2=0.43,
p=.0010)
Conclusions: The relatively large chianges in DMI pharmacokinetics suggest that rtonwivr
inhibited the CYP2D6 metabolism of DMI to 2-OH DMI. Given the narrow safety mrgin
of the TCAs, the pharmacokinetic changes are potentially cr inically relevant. During TCA and
ritonavir coadministration, aTCA dosage decrease, mo nitoring of adverse events and/or
concentration during the first several weeks should be considered.
R.J. Bertz, D4PK / API 3A, 100 Abbott Park Road, Abbott Park, IL 60064-3500 Telephone:
[phone] Fax: [phone] email: [email protected]
Mo.B.1202
CUTANEOUS ERUPTIONS ASSOCIATED WITH NEVIRAPINE (NVP) THERAPY IN
HIV-I INFECTED INDIVIDUALS
Kohlbrenner Veronika, Dransfield K, Cotton D, Robinson P Myers M. Boehringer Ingelheim
Pharmaceuticals, Ridgefield, CT
Objective: A descriptive study of HIV I infected persons taking NVP with identification of
risk factors for the development of cutaneous eruptions.
Methods: A retrospective analysis of all patients enrolled into NVP chnical trials.Those
patients experiencing cutaneous eruptions, defined as any occurrence of erythematous or
maculopapular rash, or severe blistering eruptions including Stevens-Johnson syndrome (SJS)
were categorized according to gender, race, history of prior drug experience, basehne CD4
count and use of prior or concomitant antibactenals.
Results: A total of 1407 patients received NVP For patients with unblinded dat,, iei
graphics revealed a largely gay white (83%) male (88%) population. Most were n the 250
500 CD4 cells/mm3 stratum, most were nucleoside experienced and syrmptomatic.
Cutaneous eruptions developed in 28% of patients admirnistered 200 mg b Id. following a 2
week 200 mg q.d. lead-in dose. Adjusting for the contro l group, NVP attri. tb c-ish
occurred at an incidence of 17%. Overall 84 of 1407 (6%) DAIDS Grade 3 or 4 rashes
occurred which included several cases of SJS.There was a trend for a higher incidence of
rash among patients with CD4 counts of less than 100 cells/mm3 although there ws n
increased risk of rash among patients who used TMP/SMX or amoxiclimn/clIVlanate. There
was no interaction between NVP and fluconazole, however there was a h gher rate of rash
in patients using this antifungal. For patientsexperiencing Grade 3 or 4 rashes, t ipmrticu
larly striking that the incidence of rash was lower forn patients usng TMP/SMX versus those
who did not.
Conclusion: Cutaneous eruptions are a frequent but usually benign complication of NVP
therapy in HIV infected patients with no reliable predictors.
Veronika Kohlbrenner, M.D. (203) 79 I -62 I 5 900 Ridgebury Road, PO. Box 368 Ridgefield,
CT 06877 USA.Tel.: [phone]
Mo.B. 1204
A COMPARISON BETWEEN THE RESPECTIVE IN VITRO TOXICITIES OF
SULPHAMETROLE AND SULPHAMETHOXAZOLE
Coleman Michael D*, Kohl, C*. * Aston University, Birmingham, United Kingdom; "
Hafslund Nycomed Phiarma. AG, Linz, Austria.
Objectives: to determine if sulphametrole (SMT) is less toxic in vitro compared with sulphamethoxazole (SMX).
Methods: three toxicity tests have been used, all of which depended on rat liver microsomnes (with or without the necessary NADPH for oxidative metabolism) to generate cyto
toxic metabolites of SMX and SMTThey were test I (microseomes, human mononuclear
leucocytes and either SMX or SMT; trypan blue exclusion indicates toxicity), test 2 (microsomes, human erythrocytes, drugs; methaemoglobin generation ndicates toxicity) and test 3
(mic rosomes, erythrocytes and drugs, separated by a celulose membrane n a two com
partment model; methaemoglobin indicates toxicity). Drug vehicle (methanol) concentra
tion < I% of incubation vol.). Statistical analysis was by Students't test (with Bonferron
correction); data expressed as mean + SD, n=4. -,,+ denote P < 0.05, 0.01 and 0.001.
Results:.
Test I Test 2 Test 3
No NADPH NADPH No NADPH NADP No NADPH NADPH
SMX 12.5 + 2.5 20.0 + 3.6d 0.93 + 0.2+ 15.8+ 8.8+ 056 + 0.2 32 + 05 ]
SMT I1.1 + 4.9 12.5 + 4.6 0.73 + 0.+ 6.7 + 0.2+ 0.7 + 0.3 9 + 0.2
Blacknground toxicity for test I (microsomes, vehice Itells 9.3 + 3.4%) wis no ye tigninly
diffntnnt from NADPH flee test I incubitrons. Nithem cimpound wis to r irte absence
ml NADPH. In all thtne tests with NADPH,i voiniy wasge s inlca iower wirh SMIl ter
pared with SMX. In test I, SMT showed no signiFcant toxicity Both compounds were syrnfi
cantly less toxic in test 3 compared with test 2, indicating that then metaboltes were minsuff
iently stable to retain toxicity when traversing distnce and membranes.

89