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Effect of axitinib on the QT interval in healthy volunteers.
Ruiz-Garcia, A, Houk, BE, Pithavala, YK, Toh, M, Sarapa, N, Tortorici, MA
Cancer chemotherapy and pharmacology. 2015;(3):619-28
Abstract
PURPOSE Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1-3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization. METHODS The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration-QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily). RESULTS Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope -0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was -3.0 [90 % confidence interval (CI) -5.4, -0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4-8.5) ms. The slope population mean estimate was -0.331 (95 % CI -0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445-0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia's, Bazett's, and study-specific correction methods. CONCLUSIONS Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.
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2.
Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity.
Fuchs, I, Hafner-Blumenstiel, V, Markert, C, Burhenne, J, Weiss, J, Haefeli, WE, Mikus, G
European journal of clinical pharmacology. 2013;(3):507-13
Abstract
PURPOSE The aim of this clinical study was to investigate a previously proposed mechanism of ketoconazole-mediated inhibition of cytochrome P450 3A (CYP3A) induction. METHODS A two-phase, randomized, cross-over, open, mono-centre trial was carried out. Participants received ketoconazole and St John's wort for 8 days to study the proposed suppression of St John's wort-mediated induction of CYP3A at the transcriptional level. In the second phase, we studied the inhibitory effect of a single dose of ketoconazole directly at the enzyme level during CYP3A induction by St John's wort. Midazolam served as a marker substance of CYP3A activity using an established limited sampling strategy. RESULTS After 8 days of simultaneous ketoconazole and St John's wort administration, CYP3A-mediated midazolam metabolism was strongly inhibited (81 % decrease in clearance). Following the induction of CYP3A with St John's wort (6.6-fold increase in clearance on day 8), a single dose of ketoconazole strongly inhibited midazolam metabolism to the same degree (82 % decrease in clearance in relation to baseline). An induction of midazolam metabolism was observed after discontinuation of both drugs in both study phases. These results apparently contradict the in vitro results where ketoconazole showed an inhibitory effect on the transcription of CYP3A genes. CONCLUSIONS Ketoconazole is a strong inhibitor of CYP3A, also when used concomitantly with St John's wort. In therapeutic doses it does not inhibit pregnane X receptor-mediated induction of CYP3A in vivo.
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3.
Ascending single-dose study of the safety profile, tolerability, and pharmacokinetics of bosutinib coadministered with ketoconazole to healthy adult subjects.
Abbas, R, Leister, C, El Gaaloul, M, Chalon, S, Sonnichsen, D
Clinical therapeutics. 2012;(9):2011-9.e1
Abstract
BACKGROUND Bosutinib (SKI-606) is an orally bioavailable, competitive tyrosine kinase inhibitor that selectively targets both Src and Abl tyrosine kinases. Bosutinib is metabolized primarily through the cytochrome P450 3A4 pathway. Inhibition of bosutinib metabolism by coadministration with the potent cytochrome P450 3A4 inhibitor ketoconazole could potentially increase plasma concentrations of bosutinib, allowing for the study of bosutinib tolerability at supratherapeutic concentrations in a healthy subject population. OBJECTIVE This study assessed the safety profile, tolerability, and pharmacokinetics of different dose combinations of bosutinib coadministered with ketoconazole in healthy adults, and determined whether supratherapeutic concentrations of bosutinib can be achieved with ketoconazole. METHODS This was a randomized, Phase I, double-blind, placebo-controlled, sequential-group study conducted in healthy adults. Single oral doses of bosutinib 100, 200, 300, 400, 500, and 600 mg or placebo were administered with ketoconazole and food on day 1; daily single oral doses of ketoconazole 400 mg were administered on days -1 and 1 through 4. RESULTS Forty-eight subjects were enrolled. Their mean (SD) age was 32.0 (10.7) years (range, 18-50 years). The majority of the subjects (n = 44 [92%]) were white, 2 (4%) were black or African American, and 2 (4%) were of other races. Bosutinib was associated with acceptable tolerability at doses from 100 to 600 mg, with adverse events either mild (n = 30 [63%]) or moderate (n = 12 [25%]) in severity; no subject discontinued treatment due to adverse events, and no serious events were reported. Mean (SD) values for bosutinib 100 to 600 mg ranged from 58.4 (13.3) to 426 (100) ng/mL for C(max) and 2980 (802) to 23,000 (4020) ng·h/mL for AUC(0-∞); mean AUC(0-24) and AUC(0-last) ranged from 876 (234) to 7080 (1640) ng· h/mL and from 2740 (854) to 22,200 (3630) ng · h/mL, respectively. C(max) and AUC were linear and dose proportional. Mean C(max) at 600 mg was 2.1-fold higher than the steady-state C(max) previously observed for patients with chronic myelogenous leukemia who received bosutinib 500 mg once daily with food. CONCLUSIONS Single doses of bosutinib up to 600 mg coadministered with multiple doses of ketoconazole were acceptably well tolerated in this small, selected group of healthy male volunteers. In addition, supratherapeutic exposure was achieved within this range for bosutinib when coadministered with ketoconazole. ClinicalTrials.gov identifier: NCT00777530.
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Evaluation and treatment of oral candidiasis in HIV/AIDS patients in Enugu, Nigeria.
Oji, C, Chukwuneke, F
Oral and maxillofacial surgery. 2008;(2):67-71
Abstract
INTRODUCTION Oral candidiasis is one of the common diseases seen in HIV/AIDS patients. It is rare if CD4+ cell counts are above 500 microl. Outbreaks are more common as the count drops to 100 microl. It may be more difficult to treat when CD4+ cell counts fall below 50 microl. MATERIALS AND METHODS A retrospective review of 112 HIV/AIDS patients with lesions in the mouth, head, and neck seen at the oral and maxillofacial surgery units of two public hospitals in eastern Nigeria was carried out between 2000 and 2003. The focus was on oral candidiasis patients. Twenty-nine of these patients, made up of 11 males and 18 females, had oral candidiasis. To compare the action of two drugs, namely, nystatin (a topical antifungal drug) and ketoconazole (a systemic antifungal drug), we treated 15 of the patients with nystatin in the first 2 years and the remaining 14 with ketoconazole in the following 2 years. RESULTS AND DISCUSSION Amongst the 15 patients treated with topical drugs, 7 (46.7%) had complete remission, 2 (13.3%) had partial response, 4 (26.7%) remained stationary, and 2 (13.3%) died. Out of the 14 cases treated with systemic drugs, 11 (78.6%) had complete remission, 2 (14.3%) had partial response, and 1 (7.1%) died.
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Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes.
Yong, WP, Ramirez, J, Innocenti, F, Ratain, MJ
Clinical cancer research : an official journal of the American Association for Cancer Research. 2005;(18):6699-704
Abstract
PURPOSE Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam. Its effect on UGT1A substrates is unclear. A recent study found that coadministration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecine), an UGT1A substrate. This study investigates whether ketoconazole contributes to the increase in SN-38 formation by inhibiting SN-38 glucuronidation. EXPERIMENTAL DESIGN SN-38 glucuronidation activities were determined by measuring the rate of SN-38 glucuronide (SN-38G) formation using pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7 and 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN-38G formation was measured by high-performance liquid chromatograph. RESULTS Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9. The K(i) values were 3.3 +/- 0.8 micromol/L for UGT1A1 and 31.9 +/- 3.3 micromol/L for UGT1A9. CONCLUSIONS These results show that ketoconazole is a potent UGT1A1 inhibitor, which seems the basis for increased exposure to SN-38 when coadministered with irinotecan.
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Limited utility of cyclosporine C2 monitoring in heart transplant recipients receiving ketoconazole.
Zakliczynski, M, Krynicka, A, Szewczyk, M, Wojarski, J, Zembala, M
Transplantation proceedings. 2003;(6):2333-4
Abstract
The aim of the study was to compare 2 hours postdose concentration (C2) of CyA in stable patients receiving ketoconazole concomitantly late after heart transplantation (OHT) with patients not receiving ketoconazole. Routine C2 and C1 (1 hour postdose concentration) of CyA monitoring (FPIA, AxSYM, Abbott) along with C0 (trough level) were performed in 64 elective patients. The KETO group consisted of 29 patients receiving 200 mg of ketoconazole daily along with CyA; the remaining 35 patients were included into the control group. Patient characteristics (KETO vs control group) were as follows: age, 49 +/- 11 versus 48 +/- 12 years; percentage of male patients, 93 versus 80; follow-up post-OHT, 4.3 +/- 2 versus 5.3 +/- 2 years. Target C0 of CyA was 175 to 225 ng/mL; CyA doses remained stable for at least 1 month. We compared maintenance doses of CyA, C0, C1, C2 of CyA, number of biopsy-proven acute cellular rejection (AR) during the one year and after the first year post-OHT, and creatinine in both groups. Statistical significance was assessed using Mann-Whitney U test. Results were as follows (KETO versus control group): CyA dose, 53 +/- 30 versus 216 +/- 69 mg, P <.000001; C0, 181 +/- 77 versus 160 +/- 53 ng/mL, NS; C1, 406 +/- 78 versus 803 +/- 317 ng/mL, P =.000001); C2, 397 +/- 174 versus 689 +/- 284 ng/mL, P =.000001, AR during the first year after OHT, 2.8 +/- 1.9 versus 2.3 +/- 1.6, NS; AR beyond first year after OHT, 0.2 +/- 0.5 versus 0.7 +/- 0.9, P =.03); creatinine, 181 +/- 50 versus 160 +/- 114 micromol/L NS. In conclusion; C2 monitoring in stable heart transplant recipients receiving cyclosporine and ketoconazole concomitantly late after procedure does not seem to be sufficient to estimate the immunosuppressive effect of this combination.
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The interaction of saquinavir (soft gelatin capsule) with ketoconazole, erythromycin and rifampicin: comparison of the effect in healthy volunteers and in HIV-infected patients.
Grub, S, Bryson, H, Goggin, T, Lüdin, E, Jorga, K
European journal of clinical pharmacology. 2001;(2):115-21
Abstract
OBJECTIVE The aim of this study was to compare the effect of ketoconazole, erythromycin and rifampicin on the pharmacokinetics of saquinavir soft-gelatin formulation (Fortovase; FTV) in healthy volunteers with that in HIV-infected patients at steady state after administration of 1200 mg three times daily. METHODS In two open-labelled, randomised, crossover studies pharmacokinetic parameters were calculated in healthy volunteers who received on one occasion multiple doses of 1200 mg FTV three times daily alone and on the other occasion in combination with multiple doses of either 400 mg ketoconazole once daily or 600 mg rifampicin once daily. In another open-labelled, multicentre study, 33 HIV-infected patients underwent a pharmacokinetic assessment after 36-51 weeks of treatment with FTV and were then given additionally multiple doses of either 200 mg ketoconazole once daily, 250 mg erythromycin four times daily or 600 mg rifampicin once daily. Pharmacokinetic parameters of saquinavir were determined again at the end of the combination treatment. RESULTS In healthy volunteers, coadministration of ketoconazole increased saquinavir area under the curve from time 0 to 8 h (AUC0-8 h) by 190% (95% CI: 90-343) whereas coadministration with rifampicin resulted in a decrease for AUC0-8 h by 70% (95% CI: 50-82). In HIV-infected patients, coadministration of ketoconazole and erythromycin increased AUC0-8 h of saquinavir by 69% (95% CI: 14-150) and 99% (95% CI: 33-198), respectively. When saquinavir was given together with rifampicin, exposure of saquinavir in terms of AUC0-8 h was decreased by 46% (95% CI: 18-65) compared with the baseline assessment. CONCLUSION Interactions of saquinavir with ketoconazole, erythromycin and rifampicin were observed in healthy volunteers as well as patients. The effects observed in patients, however, appear to be less pronounced. The enzyme induction caused by rifampicin might lead to subtherapeutic levels of saquinavir and this finding appears to be of clinical relevance.
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Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole.
von Moltke, LL, Durol, AL, Duan, SX, Greenblatt, DJ
European journal of clinical pharmacology. 2000;(3):259-61
Abstract
OBJECTIVE Biotransformation of triazolam to its alpha-hydroxy and 4-hydroxy metabolites by human liver microsomes in vitro was used as an index of human cytochrome P450 3A (CYP3A) activity. RESULTS The reaction was strongly inhibited by co-incubation with the viral protease inhibitors ritonavir (IC50 = 0.14 microM) and amprenavir (IC50 = 2.5 2.9 microM), and by the azole derivative ketoconazole (IC50 = 0.07 microM). Pre-incubation of microsomes with ritonavir or amprenavir increased inhibitory potency (IC50 reduced to 0.07 microM and 1.4 microM, respectively). This was not the case with ketoconazole. CONCLUSIONS Thus, ritonavir and amprenavir are highly potent mechanism-based inhibitors of human CYP3A isoforms.