Table 1.

Summary of clinical studies relating to inhibition of ATRA metabolism with ketoconazole, liarozole and talarozole. PSA, prostate specific antigen; PASI, Psoriasis Area and Severity index

Ketoconazole (KTZ)
Dose	Population	Clinical Effects	Ref.
400 mg or 600 mg po, single dose	Healthy men (n = 21)	Blunted cortisol response to ACTH infusion at 4 hrs up to 8 hrs; Returned to pre-treatment response after 16 hrs	[84]
400 mg po, tid	Metastatic prostate cancer (n = 8) with previous orchiectomy (n = 10)	No complete remissions; Stabilization or partial response achieved in 60% of patients; Pain relief occurred in most patients	[86]
400 mg po, tid	Previously untreated advanced prostate cancer (n = 12)	Significantly reduced testosterone levels which rebounded within 8 to 12 weeks; Most patients had decreased adrenal androgens and increased LH; 1 patient had partial response and 2 had improvement of symptoms	[87]
200, 400, 800 or 1200 mg KTZ po 1 hr prior to ATRA on d. 2 and 29; 45 mg/m2 ATRA po, bid until disease progression	Early-stage or advanced non-small-cell lung cancer (n = 45)	Mean plasma AUC levels of RA were significantly reduced on d. 28 compared to d. 1; pretreatment with KTZ had no effect on plasma ATRA AUC on d. 2; 400 mg dose increased d. 29 AUC of RA by 115%	[121]
400 mg KTZ po loading dose, then 200 mg po, tid with or without ATRA (45 mg/m2 po, bid) for 14 d. with crossover to ATRA alone	Advanced solid tumors (n = 13)	No objective tumor responses documented; 2 patients had stable disease and 8 had tumor progression; Cmax of KTZ >1000 ng/mL; d. 15 ATRA plasma AUC were significantly reduced compared to d. 1 with and without KTZ	[120]
200 mg KTZ po on d. 1, 12 d. washout, 200 mg K + 30 mg alitretinoin po on d. 14, 30 mg A d. 15–26, KTZ + A on d. 27, A on d. 43–56	Healthy men (n = 18)	KTZ significantly increased AUC (40%) and Cmax (60%) of alitretinoin; 4-oxometabolites not affected; Alitretinoin had no significant effect on AUC or Cmax of KTZ	[122]
Liarozole (LRZ)
Dose	Population	Clinical Effects	Ref.
300 mg po, single dose	Healthy men (n = 12)	Significantly lowered plasma testosterone for 24 hr (<2 nmol/L in 3 volunteers); Significantly reduced estradiol and aldosterone; Significantly increased LH, FSH, progesterone, 17α-hydroxyprogesterone; Cmax = 4.92 μg/ml at 1 hr; t1/2 = 3 hr	[88]
300 mg po, bid for 28 d. (0.75 mg dexamethasone po, bid for d. 14–28)	Metastatic prostate cancer (n = 6)	2 patients had >50% decrease in PSA, 2 patients had no change in PSA; 1 patient had significant volume reduction of tumor and lymph nodes; Pain was reduced in 5 patients	[89]
300 mg po, bid (n = 31); 150 mg po, bid (n = 11)	Metastatic prostate cancer in clinical relapse	Tumor volume reductions in 30% of patients; ≥50% reduction in PSA levels in 50% of patients; Pain relief in most patients; Elevated tissue RA levels	[95]
150 mg po, bid for one month, then increased to 300 mg po, bid until disease progression or severe toxicity	Metastatic prostate cancer (n = 16)	12 patients showed disease stabilization, median time to progression was 34 weeks; All patients with bone pain had pain relief in one month; 3 patients had >50% reduction in PSA and 4 patients had 25–50% reduction in PSA levels; 2 patients had reductions in size of metastatic lesions	[97]
37.5 mg po, bid at the start with dose doubling until 300 mig po, bid was reached	Metastatic prostate cancer after androgen-ablative therapy (n = 38)	Dose-escalation study to produce grade 3 toxicity; no change in testosterone or cortisol levels; dose-related increase in 11-deoxycorticosterone; there was a negative correlation between dose of LRZ and PSA levels	[103]
150 or 300 mg po, bid up to 10 months	Hormone-resistant prostate cancer (n = 55)	7 out of 15 assessable patients had ≥50% decrease in prostate volume in 300 mg group; 41% had a response in PSA levels; >50% of patients had decreased pain	[102]
300 mg LRZ po, bid compared to 100 mg cyproterone acetate (CPA) po, bid for 12–42 months	Metastatic prostate cancer in relapse (n = 321)	26% lower risk of death in patients treated with LRZ compared to CPA; 20% of patients treated with LRZ had >50% reduction in PSA levels compared to 4% in CPA group; Pain improved more in LRZ group	[100]
Study 1 – 300 mg po, bid for 6 months; Study 2 – 150 mg po, bid and increased to 300 mg po, bid at week 4	Prostate cancer; Study 1 – n = 31; Study 2 – n = 69	6 of 13 patients in Study 1 and 4 of 9 patients in Study 2 had reduced prostate size; 29% of patients had a partial or complete normalization of PSA levels; Near peak average plasma concentration was 4.67 μg/mL LRZ; Tmax for RA = 4 hrs; RA returned to pretreatment values by 8 hrs	[101]
75, 150 or 300 mg LRZ po on d. 2 and 29 1 hr prior to ATRA; 45 mg/m2 ATRA po, bid, d. 3–27 and 45 mg/m2 ATRA po, qd on d. 1,2, 28, and 29;	Patients with solid tumors (n = 26)	LRZ had no effect on ATRA AUC on d. 2 but significantly increased AUC on d. 29; LRZ may be effective in attenuating retinoid resistance when using RA to treat cancer	[111]
300 mg po, bid	Non-small cell lung cancer (n = 14)	Median survival for all patients was 3 months; the authors suggested LRZ as a single agent is ineffective for treating NSCLC	[105]
150 mg po, bid for 2 weeks, then attempted dose escalation to 300 mg po, bid until disease progression	Advanced breast cancer (postmenopausal) (n = 29)	4 patients responded to treatment and 7 patients had stabile disease; 11 patients had pain relief; estradiol and estrone levels decreased; trough drug levels ranged from 0.1 – 3.79 μg/mL at 1 month	[106]
150 mg po, bid for 2 weeks, then attempted dose escalation to 300 mg po, bid until disease progression	ER negative (n = 16), ER positive, tamoxifen-refractory (n = 16), and chemotherapy-resistant (n = 27) breast cancer	25% of patients in the first two groups were responders and 3 patients responded in the third group; Pain relief scores improved in 11 patients; Estradiol levels were suppresed; trough LRZ plasma levels ranged from 0 – 3 ng/mL at 1 month	[107]
150 mg po, bid for 2 weeks, then attempted dose escalation to 300 mg po, bid until disease progression	Chemotherapy-resistant (n = 34) and potentially hormone-sensitive (n =37) metastatic breast cancer	4 patients in chemotherapy-resistant group were partial responders; 2 complete responders and 6 partial responders in the potentially hormone sensitive group; Side effects were considered worse than hormonal agents	[108]
75 or 150 mg po, bid for 12 weeks	Severe psoriasis (n = 31)	Decreased PASI score by 45% at week 4, 60% at week 8, and 77% at week 12; 9 patients dropped out because of insufficient response or adverse event	[125]
75 mg LRZ po, bid or 25 mg acitretin po, qd for 24 weeks	Severe plaque psoriasis (n = 20)	Significant improvements in PASI score in both groups at 12 weeks; Reduction in inflammation and epidermal proliferation	[126]
75 mg po, bid for at least 2 months	Extensive plaque psoriasis (n = 7)	5 patients had improved PASI scores at 8 weeks; In responder patients, the number of actively cycling epidermal cells decreased to normal levels and the expression of differentiation markers decreased to levels of healthy volunteers; Markers of inflammation decreased with treatment	[127]
50, 75, or 150 mg po for 12 weeks	Psoriasis (n = 139)	Only 150 mg group had response rate significantly different from placebo (PASI score changed from 15.8 to 8.8 at 12 weeks)	[123]
75 mg LRZ po, bid (n = 7) or placebo (n = 8) for 12 weeks	Palmoplantar pustular psoriasis (n = 15)	4 of 7 patients on LRZ were responders; Decreased number of pustules and significantly decreased fresh pustules; Decreased severity of disease	[124]
150 mg po, bid for 12 weeks	Ichthyosis (n = 12)	Significantly reduced scaling and roughness, reduction in the extent and severity of skin lesions; Significant increase in keratin-4 after 12 weeks	[129]
5% topical LRZ on one-half of body for 6 wks then both sides for 4 wks	Hereditary ichthyosis (n = 12)	Reduced scaling and roughness of LRZ-treated skin	[130]
75–225 mg LRZ po, bid (n = 15) or 35–60 mg acitretin po (n = 17) for 12 weeks	Ichthyosis (n = 32)	10 patients in LRZ group and 13 in acitretin group showed marked improvement; No differences in symptom scores for scaling, erythema or bullae between groups at end of treatment	[128]
75 mg/d. or 150 mg/d. po LRZ or placebo	Lamellar ichthyosis vs healthy epidermis (n = 12)	Improvements in ichthyosis scores were seen at both doses; Reduction in thickness of stratum corneum and viable epidermis compared to baseline; CRABPII and KRT4 mRNA expression increased in 7 patients; KRT2 decreased in all patients; Increased CYP26A1 mRNA	[131]
300 mg po, single dose	Healthy men (n = 12)	Significantly lowered plasma testosterone for 24 hr (<2 nmol/L in 3 volunteers); Significantly reduced estradiol and aldosterone; Significantly increased LH, FSH, progesterone, 17α-hydroxyprogesterone; Cmax = 4.92 μg/ml at 1 hr; t1/2 = 3 hr	[88]
3.0% topical LRZ for 48 hrs	Healthy volunteers (n = 17)	1.3 μg LRZ/g weight wet epidermis after 18 hr and 3 μg LRZ/g after 48 hr; 19 ng RA/g wet weight at 18 hr, and 6 ng RA/g at 48 hr (not detectable in control); 3% LRZ alone increased RA 4-hydroxylase activity with a synergistic increase when co-adminstered with 0.001% RA or 0.025% retinol	[181]
Talarozole (TLZ)
Dose	Population	Clinical Effects	Ref.
0.5 to 4 mg po, bid for 8 d.	Healthy subjects	TLZ Tmax = 1 hr; t1/2 = 1.1 to 2.1 hrs; Css achieved with 24 hr of multiple dosing; Increased Cmax of RA on d. 1 and 8 at all TLZ doses compared to control	[141]
0.07 or 0.35% topical for 9 d.	Healthy subjects (n = 15)	Elevated skin levels of CRABPII, cytokeratin K4, and CYP26A1 expression and reduced cytokeratin K2e and IL-1 expression; Epidermal thickness increased with 0.35% TLZ	[140]
1 mg/d. po for 8 weeks (follow-up at 10 weeks)	Moderate to severe plaque psoriasis (n = 19)	TLZ Cp = 0.14 to 1.39 ng/ml at 2 to 4.5 hr post-dosing; >50% reduction in PASI score in 38% of patients at 8 weeks and 54% of patients at 2-week follow-up; ATRA Cp increased by 0.5 to 1.5 ng/ml from baseline 2 to 4.5 hr after dosing	[138]
0.5, 1 or 2 mg/d. po for 12 weeks	Moderate to severe plaque psoriasis (n = 176)	18.4%, 29.4%, and 37.1% of patients achieved 75% reduction in PASI score with 0.5, 1, and 2 mg doses, respectively	[141]
1 mg/d. po for 12 weeks (follow-up at 16 weeks)	Moderate to severe facial acne (n = 17)	31.5% reduction in total lesion count at 4 weeks, 76% reduction at 12 weeks, and 77.2% reduction at 16 weeks	[137]