Cannabis L. (Cannabis sativa)
The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir CSV JSON

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.

indinavir

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.

Compound measured Measurement Value 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

Population

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%)

Pharmacokinetic (PK) Sampling Information

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

Object Administration — indinavir

Oral

Capsule (not specified)

2400 mg

800 mg TID

25 days

Precipitant Administration — delta-9-tetrahydrocannabinol (THC)

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

Natural Product Characteristics

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.

nelfinavir

NFV = nelfinavir
THC = delta-9-THC

Results

Table 3. Cmax % change reported -17.4 (-43-64). AUC0-8 % change reported -10.2 (-46-92).

Compound measured Measurement Value Study sequence Additional information N replicates

Experimental Conditions

Parallel
Placebo-controlled

Population

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%)

Pharmacokinetic (PK) Sampling Information

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

Object Administration — nelfinavir

Oral

Tablet (not specified)

2250 mg

750 mg TID

25 days

Precipitant Administration — delta-9-tetrahydrocannabinol (THC)

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

Natural Product Characteristics

The National Institute on Drug Abuse

Not specified