Cannabis (Cannabis sativa)
The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir
CSV
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Background and objectives: The use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV).
Methods: Subjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline.
Results: At day 14, the 8-h area under the curve (AUC8) changed by 10.2% (P 0.15), maximum concentration (Cmax) by 17.4% (P 0.46), and minimum concentration (Cmin) by 12.2% (P 0.28) for patients in the NFV marijuana arm (n 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n 9): AUC8 had changed by 14.5% (P 0.074), Cmax by 14.1% (P 0.039), and Cmin by 33.7% (P 0.65).
Conclusion: Despite a statistically significant decrease in Cmax of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.
1 . IDV+THC PK at Baseline and Day 14 (id=NPDI-qhVkgQ)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
IDV = indiavir
THC = delta-9-THC
Baseline = control
Day 14 = test
Results
Table 2. Cmax % Change reported as -14.1 (-58 to 7), p = 0.039; AUC0-8 % change reported as -14 (-66 to 44)
Despite a statistically significant decrease in Cmax of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Inclusion criteria: at least 18 years old, have documented HIV infection, and be on a stable antire- troviral treatment regimen that included either IDV or NFV as the sole PI in addition to nucleoside and/or non-nucleoside reverse transcriptase inhibitors, for at least 8 weeks prior to enrollment. Subjects were also required to have a stable viral load, de®ned as less than a threefold change in HIV RNA level for the 16 weeks prior to enrollment. All subjects were required to have prior experience smoking marijuana (defined as six or more times) to ensure that they knew how to inhale and what neuropsychiatric effects to expect.
Exclusion criteria included the following: any active opportunistic infection or malignancy requiring acute treatment; unintentional loss of ≥10 percent of body weight during the past 6 months; current substance dependence; methadone maintenance; use of tobacco or cannabinoids (smoked or oral) within 30 days of enrollment; history of serious pulmonary disease; pregnancy; and Stage II or higher AIDS dementia complex. Laboratory exclusion criteria were hematocrit < 25% and hepatic transaminase elevations to greater than five times the upper limit of normal.
Parallel
Placebo-controlled
Females
Males
No marijuana use
Black or African American
More than one race
White
28
Patient demographics reported include subjects not taking IDV.
Nine subjects' ethnicity is reported as "mixed/other" and is not further specified.
Age (years):
- < 40: 18 (29%)
- 40 - 49: 33 (53%)
- ≥ 50: 11 (18%)
Baseline and day 14: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 hr post-dose
Empty stomach
Day 14: just prior the second marijuana cigarette; 2, 60 min, 6 hr after smoking
Drug or Natural Product Administration
Oral
Capsule (not specified)
2400 mg
800 mg TID
25 days
Inhalation
Cigarette
Up to 3 cigarettes containing 3.95% delta-9-THC
Up to three times, as tolerated, 1 hr prior to meals
21 days
The National Institute on Drug Abuse
Not specified
2 . NFV+THC PK at Baseline and Day 14 (id=NPDI-J5A-Vg)
In Vivo Interaction Study
No Effect (based on bioequivalence limits) was detected.
NFV = nelfinavir
THC = delta-9-THC
Results
Table 3. Cmax % change reported -17.4 (-43-64). AUC0-8 % change reported -10.2 (-46-92).
| Sample | Compound measured | Value | Measurement | Study sequence | Additional information | N replicates |
|---|
Experimental Conditions
Parallel
Placebo-controlled
Females
Males
No marijuana use
Black or African American
More than one race
White
34
Patient demographics reported include subjects not taking NFV.
Nine subjects' ethnicity is reported as "mixed/other" and is not further specified.
Age (years):
- < 40: 18 (29%)
- 40 - 49: 33 (53%)
- ≥ 50: 11 (18%)
Baseline and day 14: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 hr post-dose
With meals
Day 14: just prior the second marijuana cigarette; 2, 60 min, 6 hr after smoking
Drug or Natural Product Administration
Oral
Tablet (not specified)
2250 mg
750 mg TID
25 days
Inhalation
Cigarette
Up to 3 cigarettes containing 3.95% delta-9-THC
Up to three times, as tolerated, 1 hr prior to meals
21 days
The National Institute on Drug Abuse
Not specified