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Antiviral PK and Drug-Drug Interactions, Report #1
Reported for NATAP by Scott Penzak, PhD, National Institutes of Health (NIH)
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Subject Index:
1. DdI-allopurinol (gout drug)
2. Ritonavir-antipsychotic medication olanzapine
3. Methadone-ritonavir/saquinavir (1600/100 once daily)
4. Nelfinavir-LAAM/methadone
5. Methadone-delavirdine
6. Indinavir-grapefruit & orange juice
7. Amprenavir/ritonavir once & twice daily in plasma & intracellular
8. Ritonavir/saquinavir & efavirenz
Several pharmacokinetic drug interactions involving antiretroviral (ARV)
medications were reported at this year's ICAAC in Chicago (Poster Session 47
A/H; Sunday December 16, 3:00 - 4:00 pm). Liang and colleagues evaluated the
influence of allopurinol (a xanthine oxidase inhibitor for the treatment of
gout) on the pharmacokinetics of didanosine (ddI) -administered as the
buffered chewable tablet formulation- in 7 HIV-infected patients.1 Subjects
received a single oral dose of ddI (4 X 100 mg tablets) before and after 7
days of allopurinol administration. Allopurinol resulted in a 2.3 fold
increase in the ddI area under the concentration-time curve (AUC) and maximum
plasma concentration (Cmax). The exact mechanism by which allopurinol
increased ddI absorption is unknown but may be related to impaired
presystemic biotransformation of ddI due to xanthine oxidase inhibition by
allopurinol. Theoretically, this interaction may be virologically beneficial
if one assumes that active (triphosphorylated) intracellular concentrations
of the drug are proportionately elevated. However, the potential for
increased ddI toxicity (peripheral neuropathy; pancreatitis) with concurrent
allopurinol may be of greater clinical concern. Areas of continued interest
with this combination are the influence of allopurinol on ddI absorption and
disposition with repeated ddI dosing and most importantly, the influence of
allopurinol on the pharmacokinetics of didanosine enteric-coated preparation.
Based upon their cytochrome P450 (CYP) metabolic pathways, there has been
considerable speculation over the past several years regarding potential drug
interactions between ARV and antipsychotic medications. However, until now,
no pharmacokinetic studies had been conducted to confirm or refute such
speculation. Investigators reported that ritonavir (dose-escalated to 500 mg
twice daily over 11 days) decreased the AUC of a single-dose of olanzapine 10
mg by 53% in 14 HIV-negative healthy volunteers.2 Apparent oral clearance of
olanzapine increased by 116% with ritonavir. The likely mechanism of this
interaction is induction of olanzapine metabolism through CYP1A2 and
glucuronosyl tranferases by ritonavir. Because there is not a well-defined
relationship between olanzapine plasma concentrations and therapeutic effect,
the clinical implications of this interaction are not entirely clear.
Nonetheless, the large magnitude of this interaction suggests that
HIV-infected patients receiving this combination may ultimately require
higher olanzapine doses to achieve the desired therapeutic effect of the
drug. However, it must be noted that the ritonavir dose used in this study
(500 mg twice daily) exceeds that commonly used in clinical practice (100-400
mg twice daily as a pharmacokinetic enhancer). While lower doses of ritonavir
in combination with other protease inhibitors (e.g. lopinavir; indinavir;
amprenavir) might also be expected to lower olanzapine concentrations, it is
unclear whether the magnitude of the interaction will be as substantial as
that observed in this study.
Interactions between ARVs and methadone were the subject of 3 abstracts this
year.3,4,6 Shelton and colleagues examined the interaction between methadone
and a once-daily saquinavir-ritonavir (1600 mg-100 mg) regimen in 12
HIV-negative volunteers on stable methadone regimens.3 Saquinavir-ritonavir
dosing was directly observed and lasted 14 days. Unbound R-methadone (the
pharmacologically active form of the drug) was insignificantly reduced by app
roximately 8% with saquinavir-ritonavir. The extent of this interaction is
not likely to be of clinical significance. Importantly, this study analyzed
unbound R-methadone concentrations. Investigations often report R and S total
(bound + unbound) methadone concentrations, and this can make their results
difficult to assess for clinical significance. An interesting caveat to this
study was that the authors also measured saquinavir concentrations and found
them to be lower compared to concentrations achieved in other uninfected
populations receiving the same regimen. However, the saquinavir Cmin in this
study (0.12 [0.05-0.2]) was comparable to that achieved with traditional
(thrice daily) saquinavir regimens. Also, the saquinavir AUC-24 in this study
(27.7 mcg*hr/mL [20-39]) was greater compared to historical data with thrice
daily regimens (12.5 mcg*hr/mL). Further study is necessary to determine
whether the once daily saquinavir-ritonavir combination used in this study,
produces desirable pharmacokinetics in patients with HIV infection.
P.F. Smith and colleagues examined the effect of methadone and the opiate
agonist LAAM on the pharmacokinetics of nelfinavir and its pharmacologically
active M8 metabolite.4 Healthy non-HIV-infected volunteers maintained on
stable doses of either methadone (n=16) or LAAM (n=13) and
non-opiate-dependent controls (n=15) received nelfinavir 1250 twice daily for
5 days followed by pharmacokinetic sampling for nelfinavir and M8. Nelfinavir
pharmacokinetic parameter values did not differ between the groups, although
the median nelfinavir 12-hour trough was higher in methadone recipients
compared to control (3.3 vs. 1.2 mM; p< .05). The M8 AUC however, was lower
with methadone (9.5 µM/mL*h) and higher with LAAM (25.2 µM/mL*h) compared to
control (18 µM/mL*h). Because multiple CYP enzymatic pathways metabolize
nelfinavir, and M8 is formed and biotransformed by CYP enzymes, it is
difficult to tell which CYP isoform(s) methadone and/or LAAM interacted with
to produce their respective effects on nelfinavir and M8 disposition. It is
also difficult to determine the potential clinical significance (if any) of
these interactions. Because M8 has demonstrated equal potency to nelfinavir
against HIV in vitro, the authors speculate that the interaction between
methadone and nelfinavir may be of clinical relevance. However, data from a
retrospective investigation presented elsewhere at this conference suggests
that nelfinavir in combination with methadone is safe and effective in
patients co-infected with HIV and Hep-C.5
In the last of the methadone interaction studies, the pharmacokinetics of
delavirdine and its N-delavirdine metabolite were unaffected by methadone
administration in 16 healthy HIV-negative volunteers maintained on methadone
compared to 15 non-opiod-dependent controls.6 The influence of delavirdine on
methadone disposition was not evaluated
Several years ago the manufacturer of indinavir conducted a study in which
grapefruit juice administration reduced plasma concentrations of indinavir
(administered as a single 400 mg dose) by 26%;7 results from this study were
subsequently included in DHHS guidelines for the treatment of HIV infection
in adults. Two subsequent studies8,9, including one presented at this poster
session9, have shown that grapefruit juice does not alter steady-state plasma
concentrations of indinavir. Investigators administered grapefruit juice,
Seville orange juice (a known CYP3A4-inhibiting citrus juice) and water along
with indinavir to 13 healthy non-HIV-infected volunteers. Other than a delay
in indinavir absorption with Seville orange juice, indinavir pharmacokinetic
parameter values were unaffected. Results from this study suggest that
interpatient variability in indinavir absorption and disposition does not
arise from presystemic intestinal metabolism of the drug (since indinavir
concentrations were not significantly altered when intestinal CYP3A4 was
inhibited by citrus juices). The two take-home points from this study are
that (1) interpatient variability in indinavir pharmacokinetics likely arises
from variability in meal consumption with the drug, adherence, and hepatic
CYP metabolism (2) Grapefruit juice does not alter steady-state
pharmacokinetics of indinavir including Cmin, which has been associated with
virologic response.
Garraffo and coworkers investigated the influence of concurrent ritonavir on
plasma and intracellular (IC) amprenavir concentrations in 10 HIV-infected
subjects.10 Subjects received amprenavir 1200 mg twice daily, amprenavir 600
mg + ritonavir 100 mg twice daily, and amprenavir 1200 mg + ritonavir 200 mg
once daily for a minimum of 10 days. IC amprenavir concentrations were
measured pre-dose, 2, and 22 hours (only for the once daily regimen) after
dosing. As expected, plasma concentrations of amprenavir were markedly
elevated by ritonavir. Cmin was 7-fold higher with amprenavir 600 mg +
ritonavir 100 mg twice daily, and 4 fold higher with amprenavir 1200 mg +
ritonavir 200 mg once daily, compared to amprenavir 1200 mg twice daily.
Amprenavir Cmax and Tmax were unaffected by ritonavir. Of note, Cmin values
with all amprenavir regimens were above typical IC50 values of amprenavir
against HIV from multiple PI failure patients.11 The geometric mean ratio at
Cmin of IC amprenavir: plasma amprenavir was highest (3.52) for the once
daily amprenavir-ritonavir regimen, followed by the amprenavir-ritonavir
twice daily regimen (2.47); IC amprenavir concentrations were below the limit
of quantitation for the amprenavir 1200 mg twice daily regimen. Increased
concentrations of IC amprenavir with ritonavir may be due to cellular
inhibition of the MDR-1 transporter P-glycoprotein by ritonavir; induction of
an influx mechanism by ritonavir is also possible since amprenavir IC:Plasma
ratios exceeded 1.0 with concurrent ritonavir. Results from this study
provide further support for the feasibility for once daily dosing with an
amprenavir-ritonavir combination. This combination has a desirable
pharmacokinetic profile and a reduced pill burden that may improve compliance
with amprenavir. Also, it is encouraging that intracellular concentrations
were highest with the once-daily amprenavir-ritonavir regimen; however, the
clinical significance of intracellular protease inhibitor concentrations is
not entirely clear and continues to be a focus of debate among
pharmacologists.
Lastly, Piliero et. al. reported on the pharmacokinetics of
saquinavir-ritonavir with and without concurrent efavirenz.12 Twelve
non-HIV-infected healthy subjects received saquinavir-ritonavir (400 mg each)
twice daily for 10 days (days 1-10) followed by the combination of
saquinavir-ritonavir plus efavirenz (600 mg daily) on days 10-24.
Pharmacokinetic sampling for saquinavir was done on days 10 (without
efavirenz) and 24 (with efavirenz). The (arithmetic?) mean Cmin day 24:day 10
ratio was 0.91; however the standard deviation (0.46) was large. AUC ratios
of saquinavir on days 10 and 24 were not reported. Efavirenz Cmin
concentrations, measured on day 24, were in agreement with historical data.
The authors analyzed the likelihood of free saquinavir Cmin concentrations
(defined as 10% of plasma Cmin) exceeding various EC95 concentrations; they
found no significant difference after the addition of efavirenz. Results from
this investigation are consistent with previous pharmacokinetic data with
saquinavir-ritonavir-efavirenz13, both suggesting that efavirenz does not
appreciably reduce saquinavir exposure when administered as
saquinavir-ritonavir 400 mg twice daily.
References
1. Liang D, Breeaux K, Rodriguez M et. al. Allopurinol increases didanosine
(ddI) absorption in HIV-infected patients. In: Abstracts of the 41st
Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago,
IL, USA. December 16-19, 2001 [A-498].
2. Penzak SR, Lawhorn WD, Hon YY et. al. influence of ritonavir and CYP1A2
genotype on olanzapine disposition in healthy subjects. In: Abstracts of the
41st Interscience Conference on Antimicrobial Agents and Chemotherapy.
Chicago, IL, USA. December 16-19, 2001 [A-493].
3. Shelton MJ, Cloen D, Bereson C et. al. Pharmacokinetics (PK) of once daily
(QD) saquinavir/saquinavir (SQV/RTV): Effects on unbound methadone and alpha
1-acid glycoprotein (AAG). In: Abstracts of the 41st Interscience Conference
on Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19,
2001 [A-492].
4. Smith PF, Booker BM, Difrancesco R et. al. Effect of methadone or LAAM on
the pharmacokinetics of nelfinavir and M8. In: Abstracts of the 41st
Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago,
IL, USA. December 16-19, 2001 [A-491].
5. Brown LS, Chu M, Aug C et. al. The use of nelfinavir and twi nucleosides
concomitantly with methadone is effective and well-tolerated in HepC
co-infected patients. In: Abstracts of the 41st Interscience Conference on
Antimicrobial Agents and Chemotherapy. Chicago, IL, USA. December 16-19, 2001
[I-206].
6. Booker B, Smith P, Forrest A et. al. Lack of effect of methadone (MET) on
pharmacokinetics (PK) of delavirdine (DLV) and N-delavirdine (NDLV). In:
Abstracts of the 41st Interscience Conference on Antimicrobial Agents and
Chemotherapy. Chicago, IL, USA. December 16-19, 2001 [A-490].
7. Merck and Company. Crixivan (indinavir sulfate) package insert. West point
PA, 1998.
8. Shelton MJ, Wynn HE, Hewitt RG, DiFrancesco R. Effects of grapefruit juice
on pharmacokinetic exposure to indinavir in HIV-positive subjects. J Clin
Pharmacol 2001;41:435-42.
9. Effect of Seville orange juice (SOJ) and grapefruit juice (GFJ) on indina
vir (IDV) pharmacokinetics (PK) in healthy volunteers. In: Abstracts of the
41st Interscience Conference on Antimicrobial Agents and Chemotherapy.
Chicago, IL, USA. December 16-19, 2001 [A-488].
10. Garraffo R, Demarles D, Durant J et. al. Amprenavir (APV) plasma and
intracellular concentrations whencoadministered with ritonavir (RTV) in twice
and once daily regimen in HIV-1 infected patients. In: Abstracts of the 41st
Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago,
IL, USA. December 16-19, 2001 [A-489].
11. Sadler BM, Piliero PJ, Preston SL et. al. Pharmacokinetic drug
interaction between amprenavir (APV) and ritonavir (RTV) in HIV-seronegative
subjects after multiple, oral dosing. Presented at the 7th Conference on
Retroviruses and Opportunistic Infections, San Francisco, CA, USA, February
2000 [Abstract 77].
12. Piliero PJ, Preston SL, Japour A et. al. Pharmacokinetics of the
combination of ritonavir (RTV) plus saquinavir (SQV), with and without
efavirenz (EFZ), in healthy volunteers. In: Abstracts of the 41st
Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago,
IL, USA. December 16-19, 2001 [A-495].
13. Hendrix CW et. al. Pharmacokinetics of the triple combination of
saquinavir, ritonavir, and efavirenz in HIV positive patients. Presented at
the 7th Conference on Retroviruses and Opportunistic Infections, San
Francisco, CA, USA, February 2000 [Abstract 79].
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