Pharmacokinetics Of All-trans Retinoic Acid Research Articles

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1–15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6–15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

Pharmacokinetics of all-trans retinoic acid in Japanese patients with acute promyelocytic leukemia

Pharmacokinetics of all-trans retinoic acid in Japanese patients with acute promyelocytic leukemia

Evaluation of the Pharmacokinetics of All-Trans-Retinoic Acid (ATRA) in Wistar Rats After Intravenous Administration of ATRA Loaded into Tributyrin Submicron Emulsion and its Cellular Activity on Caco-2 and HepG2 Cell Lines

The pharmacokinetics of all-trans-retinoic acid (ATRA), an anti-cancer drug was highly variable due to its poor aqueous solubility. In this study, we investigated the pharmacokinetics of ATRA in male Wistar rats following intravenous administration of the ATRA loaded tributyrin emulsion. In vitro, the ATRA emulsion was proved binding to apolipoprotein(s). In vivo, the clearance of ATRA was significantly reduced by formulating into the tributyrin emulsion, leading to higher AUCs. Co-administration with 17α-ethynylestradiol, a compound known to upregulate the activity of low-density lipoprotein receptors in tissues, significantly increased the Ke, V, and CL of ATRA. The variation of plasma AUCs after administering the ATRA emulsion to the healthy rats was two times less than that after the ATRA solution. The IC50 in ATRA of the ATRA emulsion for the Caco-2 carcinoma cells was 3.8µg/mL lower than 6µg/mL of the ATRA solution. The IC50 of the emulsion for the HepG2 carcinoma cells was 2.8µg/mL, while IC50 was not achieved with the ATRA solution over the test concentration range. The finding indicated that the tributyrin emulsion could be used as a carrier for ATRA and enhances the drug effect by reducing the clearance and increasing the in vitro activity. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2844–2853, 2008

Effect of cytochrome P450 inhibitors (diethyl dithiocarbamate, ketoconazole and grapefruit juice) on the pharmacokinetics of all- trans-retinoic acid

Diethyl dithiocarbamate (DEDTC) has been reported to be a more powerful inhibitor of all- trans-retinoic acid (ATRA) in vitro metabolism than the well-established cytochrome P450 (CYP) inhibitor ketoconazole (KC). In recent years grapefruit juice (GJ) has been shown to be able to increase the oral bioavailability of several drugs by inhibiting intestinal CYP. This study investigated the in vivo effect of these CYP inhibitors on the pharmacokinetics of ATRA. The latter was administered to rats as a constant-rate intravenous (i.v.) infusion (0.48 mg h –1 kg –1) during 10 h and orally (1.6 mg kg –1). DEDTC (320 mg kg –1 × 2 i.v., 6.4 and 32 mg kg –1 per os (p.o.)) did not change the ATRA concentration–time profiles, whereas KC (320 and 32 mg kg –1 p.o.)—with i.v. infused or orally dosed ATRA—increased the mean concentration–time curve value by 160% and 78%, respectively. A high dose of DEDTC (320 mg kg –1 p.o.) caused a marked decrease in plasma levels of ATRA. GJ (6.4 ml kg –1 p.o.) did not affect the plasma levels of ATRA. It is concluded that the in vivo effect of CYP inhibitors (DEDTC and KC) on the elimination rate of ATRA is qualitatively different from that expected from in vitro studies.

All-trans retinoic acid and interferon-α in the treatment of a patient with resistant metastatic osteosarcoma

A boy age 14 years who was in complete remission from Stage IIB small cell osteosarcoma, which was misdiagnosed as Ewing sarcoma and consequently was treated, developed inoperable lung metastases when he was off therapy. He received second-line treatment for recurrent Ewing sarcoma, including chemotherapy and radiotherapy, and obtained only a temporary response. A compassionate treatment with all-trans retinoic acid (ATRA) and interferon-alpha (IFNalpha) was then undertaken.The patient initially was treated according to the national SE91 protocol for nonmetastatic Ewing sarcoma. After a bilateral pulmonary recurrence, he received second-line chemotherapy and irradiation of the largest metastasis, with a temporary partial response. The patient was then treated with a combination of oral ATRA (90 mg/m(2) for 3 days per week) and subcutaneous IFNalpha (3 x 10(6) U/m(2) 5 days per week) for 4 months. The same therapy also was administered for the control of residual disease after surgery for a total duration of 1 year of ATRA/IFN treatment. During the first 3 weeks of therapy, ATRA pharmacokinetics were studied.After progression of the patient's disease, despite the administration of first-line and second-line chemotherapy, combined treatment with ATRA/IFNalpha yielded a partial remission, which allowed surgical resection of the largest metastasis. The same therapy was effective in preventing tumor recurrence after incomplete removal of the remaining metastases. Treatment was well tolerated, and the patient is in stable complete remission 14 months after the end of therapy. The pharmacokinetics results confirmed the indication of an intermittent schedule for oral ATRA therapy.ATRA/IFNalpha treatment may be considered as an alternative approach in the treatment of patients with metastatic osteosarcoma who have disease that is resistant to conventional chemotherapy and in the treatment of patients with minimal tumor residue.

Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes

Cytochromes P450 (CYPs) catalyze the 4-hydroxylation of all- trans-retinoic acid (ATRA), an agent used in the treatment of certain malignancies. Literature studies have implicated several CYPs in this reaction, but the relative importance of individual CYPs is unclear. Human microsomal CYPs that contribute to the activity were evaluated by correlation with activities of hepatic drug-metabolizing CYPs, the capacity of cDNA-derived CYPs to catalyze the reaction, and inhibition of the microsomal activity by chemicals. 4-HydroxyATRA formation in microsomes varied 7-fold (8.7 to 61 pmol/mg protein/min) and correlated partially with activities mediated by CYPs 3A, 2C, and 1A (ρ = 0.53 to 0.66). cDNA-derived CYPs 2C8, 2C9, and 3A4, but not 1A1 or 1A2, catalyzed ATRA 4-hydroxylation (2.53, 4.68, and 1.29 pmol/pmol CYP/hr). The K m for the reaction was 9 ± 3 μM in hepatic microsomes (N = 3) and 6 μM in microsomes containing cDNA-derived CYP2C8; by comparison, K m values for the activity mediated by CYPs 2C9 and 3A4 were 100 and 74 μM, respectively. Inhibition of microsomal ATRA 4-hydroxylation was elicited by chemicals that interact with CYP2C8 (paclitaxel and diclofenac), but not those that interact with CYP2C9 (sulfaphenazole, tolbutamide, and torasemide). The CYP3A inhibitor troleandomycin and an anti-CYP3A IgG inhibited the activity slightly. Greater inhibition was produced by the less selective CYP3A inhibitors parathion, quinidine, and ketoconazole; CYP1A inhibitors were ineffective. These findings suggest that CYP2C8 is a major contributor to ATRA 4-hydroxylation in human liver and that 3A subfamily CYPs may be minor participants. Individual variation in CYP2C8 and 3A4 expression may influence ATRA pharmacokinetics and drug interactions during therapy.

Pharmacokinetics of all-trans retinoic acid (ATRA) in patients with renal cancer concomitantly treated with interferon alpha 2A (IFN)

Abstract Eight patients with advanced renal cell cancer were treated in a phase II trial with interferon alpha 2a (9–18 MIU/m 2 subcutaneously) three days a week and all-trans retinoic acid (ATRA) 100 mg/m 2 /day orally in three equal fractions 7 h apart. All eight patients underwent pharmacokinetic studies on day 1 of therapy, and six were again studied on day 90. A new simple and rapid HPLC method was developed to measure plasma concentrations of ATRA, with a detection limit of 5 ng/ml at 340 nm. Blood samples were drawn for 7 h following 1/3 oral doses of 100 mg ATRA/m 2 . On day 1, peak plasma levels of ATRA (56 ± 37 ng/ml, mean ± SD) were reached after 1–5.5 h. Classically, a significant decrease in both peak plasma levels and the area under the concentration-time curve was observed after 2–6 weeks of ATRA treatment. In our preliminary study, concomitant IFN treatment increased peak plasma levels of ATRA after at least 3 months of treatment in 4 patients and reduced the clearance rate in 4 patients. On day 90, a patient who had not taken INF the previous day and in whom ATRA was undetectable developed a clinical relapse.

All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: intracellular concentrations and biologic response relationship.

This study investigated the in vitro pharmacologic behavior and disposition kinetics of all-trans retinoic acid (ATRA) in acute myeloid leukemic (AML) cells, their sensitivity to its differentiating effect, and the in vivo response of acute promyelocytic leukemia (APL) patients after therapy. Fresh leukemic cells from 14 AML patients (nine APL and five non-APL), were incubated in suspension culture in the absence or presence of 10(-6) mol/L ATRA. Intracellular ATRA concentration and ATRA metabolism was determined by high-performance liquid chromatography (HPLC). Immediate uptake is observed with maximal intracellular levels (Cmax) achieved after 24 hours of incubation. At this time, ATRA levels were variable, ranging from 20 to 230 pmol/10(6) cells (median, 100 pmol/10(6) cells). Comparison of ATRA intracellular levels with the in vitro response of patients' cell samples as measured by the percentage of nitro blue tetrazolium (NBT)-positive cells after a 3-day incubation period allowed us to discriminate a group of APL patients (n = 6) with high Cmax (group A; median, 200 pmol/10(6) cells) and maximal differentiation at day 3 (median, 80%), and a group of patients (n = 8, three APL and five non-APL) with low Cmax (group B; median, 35 pmol/10(6) cells) and poor in vitro response (median, 40%; APL cases only). Interestingly, all APL patients, except one included in group A (rapid in vitro ATRA uptakers), achieved a complete remission. These findings suggest that intracellular ATRA concentrations are determinant for ATRA response and should be taken into account when monitoring the efficacy of ATRA differentiation therapeutic trials in malignant disorders.

4-oxo retinoic acid for refractory acute promyelocytic leukemia in children with all-trans retinoic acid therapy.

Therapy with all-trans retinoic acid (ATRA) achieves complete remission in a high proportion of patients with acute promyelocytic leukemia (APL), but the efficacy is reported to relate to plasma ATRA level after oral administration. The pharmacokinetics of ATRA and 4-oxo all-trans retinoic acid (4-oxo ATRA), a metabolite of ATRA, were studied in four children with APL at the time of initial oral administration. After administration of ATRA at a dose of 30 mg/m2, the peak plasma ATRA level was 20-741 ng/ml and was reached at 60-120 min. The patient with the lowest peak plasma level did not achieve complete remission and had a very high 4-oxo ATRA level compared to the patients with complete remission. These findings suggest that accelerated metabolism of ATRA plays a role in the failure of this agent in the patients without remission.