Dronabinol oral solution in the management of anorexia and weight loss in AIDS and cancer

Figures & data

Table 1 Bioequivalence and cancer-associated anorexia or weight loss dataa

Study	Population	Duration (weeks)	Total number of patients	Treatment groups (n)	Pertinent clinical outcomes	Adverse events	Discontinued due to AE
Bioequivalence data^Citation8,Citation21
Parikh et al,^Citation21 2016	Healthy volunteers	4	51 (crossover study)	Dronabinol oral solution: 4.25 mg daily (n=51) Dronabinol capsule: 5 mg daily (n=51)	Dronabinol PK (Replicate I) Cmax (ng/mL) • Soln: 1.81 • Cap: 2.20 Tmax (hours) • Soln: 1.5 • Cap: 1.0 AUC0–∞ (hours×ng/mL) • Soln: 3.75 • Cap: 3.85 t1/2 (hours) • Soln: 5.41 • Cap: 2.68	Nausea, dizziness, somnolence, headache	None
Oh et al,^Citation8 2017	Healthy volunteers	2	54 (crossover study)	Dronabinol oral solution: 4.25 mg daily (n=52) Dronabinol capsule: 5 mg daily (n=54)	Dronabinol PK (Fed) Tlag (hours) • Soln: 0.15 (CV=49.3%) • Cap: 2.02 (CV=70.2%) Tmax (hours) • Soln: 7.67 (CV=44.7%) • Cap: 5.59 (CV=58%) Cmax (ng/mL) • Soln: 1.52 (CV=63.5%) • Cap: 2.60 (CV=67.1%) AUC0–∞ (hours×ng/mL) • Soln: 10.25 (CV=36.9%) • Cap: 12.21 (CV=39.6%) t1/2 (hours) • Soln: 9.35 (CV=71.9%) • Cap: 10.4 (CV=88.7%)	Headache, euphoric mood	None
Cancer-associated anorexia or weight loss data^Citation26^–^Citation29
Plasse et al,^Citation26 1991b	Cancer	Study 1: 3 Study 2: 6	42	Dronabinol capsule 2.5 mg daily (n=8)(b/)Dronabinol capsule 2.5 mg BID (n=9)(b/)Dronabinol capsule 5 mg daily (n=19)(b/)Dronabinol capsule 2.5 mg BID (n=6)	Increased appetite:(b/)• A trend of increased appetite was noted from baseline in 2.5 mg BID group (p=0.08)(b/)• 2.5 mg BID group was associated with improved appetite when compared to 2.5 or 5 mg daily (p<0.05)(b/)Weight gain/change:(b/)• No significant weight gain between groups(b/)• Reduction in the rate of weight loss was found between 2.5 and 5 mg daily (p<0.05)	Dizziness, memory or mood changes, psychotropic effects	10 (24%) 1 in each dronabinol 2.5 mg daily and BID and the remainder in higher doses
Nelson et al,^Citation27 1994	Cancer	4	18	Dronabinol capsule 2.5 mg TID (n=18)	Improved appetite: • 13 of 18 patients	Slurred speech, nausea	3
Jatoi et al,^Citation28 2002	Cancer	Varied	469	Megestrol acetate: 800 mg daily (n=159) Dronabinol capsule: 2.5 mg BID (n=152) Megestrol acetate 800 mg daily+dronabinol capsule 2.5 mg BID: (n=158)	Increased appetite: • 75% megestrol acetate vs 49% dronabinol (p=0.0001) • 75% megestrol acetate vs 66% megestrol acetate+dronabinol (p=0.17) Weight gain: • 11% megestrol acetate vs 3% dronabinol (p=0.02) • 11% megestrol acetate vs 8% megestrol acetate+dronabinol (p=0.43)	Impotence: 18% megestrol acetate vs 4% dronabinol (p=0.002) Other effects NS difference	Megestrol acetate: 45% Dronabinol: 58% Megestrol acetate+dronabinol: 41%
Strasser et al,^Citation29 2006	Cancer	6	243	CE BID: (n=95) Dronabinol: 2.5 mg BID (n=100) Placebo: BID (n=48)	Increased appetite: • CE: 73% • Dronabinol: 58% • Placebo: 69% (p=NS between the groups)	NS difference	Not reported

Notes:

a Data on the use of dronabinol in HIV/AIDS appetite stimulation previously reviewed.^1–3

b Data reported as combined.

Abbreviations: AE, Adverse event; AIDS, acquired immunodeficiency syndrome; AUC_0–∞, area under the plasma concentration–time curve from time zero to infinity; AUC_0–t, area under the plasma concentration–time curve from time zero to the last measurable concentration; BID, twice daily; Cap, capsule; CE, Cannabis extract (dronabinol 2.5 mg+cannabidiol 1 mg); C_max, peak plasma concentration; CV, intraindividual coefficient of variability; HIV, human immunodeficiency virus; NS, not significant; PK, pharmacokinetics; Soln, solution; t_1/2, half-life; TID, three times daily; T_lag, time to the first measurable concentration; T_max, time to maximum plasma concentration.

Table 2 Pharmacotherapy and pharmacokinetic considerations with dronabinol^9,10

	Dronabinol oral capsule^Citation9	Dronabinol oral solution^Citation10
Dosage forms	• 2.5, 5, and 10 mg capsules	• 5 mg/mL solution
Storage	• Packaged in a well-closed container • Stored in a cool environment between 8°C and 15°C (46°F and 59°F) • Can be refrigerated, but not frozen	• Keep solution and syringe in the supplied carton • Refrigerated between 2°C and 8°C (36°F and 46°F) • Opened bottle can be stored at room temperature 25°C (77°F) • Discard unused portion 28 days after first opening
Initial dose (adults)	• Anorexia-associated weight loss in adults with AIDS: 2.5 mg PO BID, 1 hour before lunch and dinner • CINV in adults failing conventional antiemetics: 5 mg/m^2 PO 1–3 hours prior to chemotherapy, then every 2–4 hours after chemotherapy, not to exceed six doses/day. First dose should be taken on an empty stomach and subsequent doses may be taken without regards to meals	• Anorexia-associated weight loss in adults with AIDS: 2.1 mg PO BID, 1 hour before lunch and dinner • CINV in adults failing conventional antiemetics: 4.2 mg/m^2 PO 1–3 hours prior to chemotherapy, then every 2–4 hours after chemotherapy, not to exceed six doses/day. First dose should be taken on an empty stomach and subsequent doses may be taken without regards to meals
Initial dose (elderly and patients unable to tolerate initial dosing recommendations)	• Anorexia-associated weight loss in adults with AIDS: 2.5 mg PO once daily 1 hour before dinner or bedtime • CINV in adults failing conventional antiemetics: 2.5 mg/m^2 once daily 1–3 hours prior to chemotherapy	• Anorexia-associated weight loss in adults with AIDS: 2.1 mg PO once daily 1 hour before dinner or bedtime • CINV in adults failing conventional antiemetics: 2.1 mg/m^2 once daily 1–3 hours prior to chemotherapy
Maximum dose	• Anorexia-associated weight loss in adults with AIDS: 10 mg BID • CINV in adults failing conventional antiemetics: 15 mg/m^2 per dose, not exceeding six doses/day	• Anorexia-associated weight loss in adults with AIDS: 8.4 mg BID • CINV in adults failing conventional antiemetics: 12.6 mg/m^2 per dose, not exceeding six doses/day
Contraindications	• Hypersensitivity to dronabinol or sesame oil	• Hypersensitivity to dronabinol or alcohol • Patients on disulfiram- or metronidazole-containing products within 14 days
Bioavailability	10%–20%
Onset of action (hours)	• 0.5–1	• 0.25
Half-life (hours)	• 4	• 5.6
Cmax (ng/mL)	• 2.5 mg BID=1.3 • 5 mg BID=2.96 • 10 mg BID=7.88	• 2.1 mg BID=1.9
Tmax (hours)	• 2.5 mg BID=1.0 • 5 mg BID=2.5 • 10 mg BID=1.5	• 2.1 mg BID=1.0
Metabolism	• Liver: extensive first-pass • CYP2C9 and CYP3A4
Drug interactions	• Inhibitors and inducers of CYP2C9a and CYP3A4 may affect the levels of dronabinol 1. Darunavir, atazanavir, ritonavir, and elvitegravir/cobicistat appear to potentially increase the levels of dronabinol, whereas etravirine and efavirenz may potentially reduce the levels of dronabinol 2. Monitor increased adverse drug events associated with dronabinol, as well as adequate appetite stimulation • Highly protein-bound drugs: dronabinol is a highly protein-bound drug and may displace other protein-bound drugs, increasing their exposure. Monitor the levels of warfarin, cyclosporine, and so on • Other drugs thought to interact: disulfiram, fluoxetine, theophylline, barbiturates, benzodiazepines, amitriptyline, amphetamines, cocaine, metronidazole, anticholinergics, and other CNS depressants
Elimination	• ~50% feces • ~10%–15% urine • <5% unchanged
Effects of food	• Food appears to increase Cmax, t1/2, AUC0–t, and AUC0–∞, but slows how long it takes for dronabinol to be detected in the plasma	• With administration of a high-fat meal (59 g fat, 950 calories), there was a 2.5-fold increase in AUC0–∞, a 5-hour delay in Tmax, and a 20% decrease in Cmax

Notes:

a For individuals with the CYP2C9 genetic polymorphism, clearance may be decreased with associated systemic effects increased. Monitor for increased adverse effects.

Abbreviations: AIDS, acquired immunodeficiency syndrome; AUC_0–∞, area under the plasma concentration–time curve from time zero to infinity; AUC_0–t, area under the plasma concentration–time curve from time zero to the last measurable concentration; BID, twice daily; CINV, chemotherapy-induced nausea and vomiting; C_max, peak plasma concentration; CNS, central nervous system; CYP, cytochrome P450; PO, oral administration; t_1/2, half-life; T_lag, time to the first measurable concentration; T_max, time to maximum plasma concentration.

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