Phase I clinical and pharmacokinetic/pharmacogenetic study of a triplet regimen of S-1/irinotecan/oxaliplatin in patients with metastatic colorectal or gastric cancer

Purpose

We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC).

Methods

Patients received escalating doses of S-1 (30–40 mg/m² b.i.d.) orally on days 1–14, an escalating dose of intravenous irinotecan (120–150 mg/m²) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m²) on day 1 every 3 weeks.

Results

Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m² b.i.d., irinotecan 150 mg/m², and oxaliplatin 85 mg/m²) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first-line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5-fluorouracil to tegafur).

Conclusions

The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC.     

Clinical and Radiological Comparison of Femur and Fibular Allografts for the Treatment of Cervical Degenerative Disc Diseases

Objective

This consecutive retrospective study was designed to analyze and to compare the efficacy and outcomes of anterior cervical discectomy and fusion (ACDF) using a fibular and femur allograft with anterior cervical plating.

Methods

A total of 88 consecutive patients suffering from cervical degenerative disc disease (DDD) who were treated with ACDF from September 2007 to August 2010 were enrolled in this study. Thirty-seven patients (58 segments) underwent anterior interbody fusion with a femur allograft, and 51 patients (64 segments) were treated with a fibular allograft. The mean follow-up period was 16.0 (range, 12-25) months in the femur group and 19.5 (range, 14-39) months in the fibular group. Cage fracture and breakage, subsidence rate, fusion rate, segmental angle and height and disc height were assessed by using radiography. Clinical outcomes were assessed using a visual analog scale and neck disability index.

Results

At 12 months postoperatively, cage fracture and breakage had occurred in 3.4% (2/58) and 7.4% (4/58) of the patients in the femur group, respectively, and 21.9% (14/64) and 31.3% (20/64) of the patients in the fibular group, respectively (p<0.05). Subsidence was noted in 43.1% (25/58) of the femur group and in 50.5% (32/64) of the fibular group. No difference in improvements in the clinical outcome between the two groups was observed.

Conclusion

The femur allograft showed good results in subsidence and radiologic parameters, and sustained the original cage shape more effectively than the fibular allograft. The present study suggests that the femur allograft may be a good choice as a fusion substitute for the treatment of cervical DDD.     

Pharmacokinetic interaction of telmisartan with s-amlodipine: an open-label, two-period crossover study in healthy Korean male volunteers

BackgroundTelmisartan belongs to a class of orally active angiotensin II receptor blockers (ARBs), and S-amlodipine is an enantiomer of amlodipine. Amlodipine is a racemic mixture and the calcium channel blocking (CCB) effect is confined to S-amlodipine, whereas R-amlodipine has a 1000-fold lower activity and no racemization occurs in vivo in human plasma. Combination therapy of ARBs with CCBs provides advantages for blood pressure control and vascular protection over monotherapy.ObjectiveTo investigate the effects of coadministration of telmisartan and S-amlodipine on the steady-state pharmacokinetic properties of each drug as a drug–drug interaction study required before developing the fixed-dose combination agent.MethodsThis study comprised 2 separate parts, A and B; each was a multiple-dose, open-label, 2-sequence, 2-period, crossover study in healthy male Korean volunteers. In part A, volunteers were administered 80 mg of telmisartan, either alone or with 5 mg of S-amlodipine. In part B, volunteers were administered 5 mg of S-amlodipine, either alone or with 80 mg of telmisartan. Blood samples were taken on days 9 and 37, following the final dose of each treatment, and at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours after administration in part A, and were taken at 0 (predose), 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, and 24 hours after administration in part B. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic properties of each drug after coadministration of telmisartan and S-amlodipine were compared with those of each drug administered alone. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews.ResultsFifty-six volunteers were enrolled (32 in part A and 24 in part B), and all completed except 4 volunteers (3 withdrawn in part A and 1 withdrawn in part B). The geometric mean ratios (GMRs) (90% CI) for the C_max,ss and AUC_τ,ss of telmisartan (with or without S-amlodipine) were 1.039 (0.881–1.226) and 1.003 (0.926–1.087), respectively. The GMRs (90% CI) for C_max,ss and AUC_τ,ss of S-amlodipine (with or without telmisartan) were 0.973 (0.880–1.076) and 0.987 (0.897–1.085). Total 11 adverse events (AEs) were reported in 7 volunteers (21.9%) in part A. A total of 9 AEs were reported in 6 volunteers (25.0%) in part B. Statistical analysis confirmed that the 90% CIs for these pharmacokinetic parameters were within the commonly accepted bioequivalence range of 0.8 to 1.25, indicating that the extent of bioavailability of S-amlodipine was not affected by telmisartan. The intensity of all AEs was considered to be mild, and there were no significant differences in the prevalences of AEs between the 2 formulations.ConclusionsFollowing multiple-dose coadministration of high doses of telmisartan and S-amlodipine, the steady-state pharmacokinetic properties of telmisartan were not significantly affected, and telmisartan had no significant effect on the pharmacokinetic properties of S-amlodipine at steady state in these selected groups of healthy volunteers. Both formulations were generally well-tolerated. ClinicalTrials.gov identifiers: NCT01356017 and NCT01356043.     

Lack of any association between functionally significant <Emphasis Type="Italic">CYP2D6</Emphasis> polymorphisms and clinical outcomes in early breast cancer patients receiving adjuvant tamoxifen treatment

Active metabolites of tamoxifen are formed mainly by the action of cytochrome P450 2D6 (CYP2D6). Since there are controversies regarding associations between CYP2D6 polymorphisms and outcomes among women with early breast cancer (EBC) treated with tamoxifen, the present evaluation of links with clinical outcomes was conducted. We analyzed a total of 716 patients treated with tamoxifen for hormone receptor positive EBC between 2001 and 2005 at the National Cancer Center, Korea. All patients received tamoxifen 20 mg/day for more than 6 months. DNA obtained from whole blood samples was genotyped for CYP2D6 variants associated with reduced (*10, *41) and absent (*5) activity. Of the total of 716 patients, 558 (77.9%) received adjuvant or neoadjuvant chemotherapy prior to the tamoxifen therapy. From the genotyping of CYP2D6, 152 (21.2%) patients were classified as having the wild type (W/W), 376 (52.7%) one variant allele (W/V), and 188 (26.1%) two variant alleles (V/V). Seventy (9.8%) patients experienced disease recurrence with a median follow-up of 5.6 (range, 0.6–10.3) years. Although known prognostic factors, including tumor size, nodal status, Ki67, PgR negativity, and HER2 positivity showed strong associations with the recurrence free survival (RFS) in this population, no significant association with any of the CYP2D6 genetic variants was evident (P = 0.61; hazard ratio [HR] = 1.14; 95% CI 0.68–1.92). This remained the case after subgroup analysis according to different adjuvant treatments. Polymorphisms of CYP2D6 were not associated with clinical outcomes in EBC patients receiving adjuvant tamoxifen treatment.     

Comparison of the Efficacy and Safety of a Pharmacokinetic Model-Based Dosing Scheme Versus a Conventional Fentanyl Dosing Regimen For Patient-Controlled Analgesia Immediately Following Robot-Assisted Laparoscopic Prostatectomy: A Randomized Clinical Trial

Conventional, intravenous, patient-controlled analgesia, which is only administered by demand bolus without basal continuous infusion, is closely associated with inappropriate analgesia. Pharmacokinetic model-based dosing schemes can quantitatively describe the time course of drug effects and achieve optimal drug therapy. We compared the efficacy and safety of a conventional dosing regimen for intravenous patient-controlled analgesia that was administered by demand bolus without basal continuous infusion (group A) versus a pharmacokinetic model-based dosing scheme performed by decreasing the dosage of basal continuous infusion according to the model-based simulation used to achieve a targeted concentration (group B) following robot-assisted laparoscopic prostatectomy.In total, 70 patients were analyzed: 34 patients in group A and 36 patients in group B. The postoperative opioid requirements, pain scores assessed by the visual analog scale, and adverse events (eg, nausea, vomiting, pruritis, respiratory depression, desaturation, sedation, confusion, and urinary retention) were compared on admission to the postanesthesia care unit and at 0.5, 1, 4, 24, and 48 h after surgery between the 2 groups. All patients were kept for close observation in the postanesthesia care unit for 1 h, and then transferred to the general ward.The fentanyl requirements in the postanesthesia care unit for groups A and B were 110.0 ± 46.4 μg and 77.5 ± 35.3 μg, respectively. The pain scores assessed by visual analog scale at 0.5, 1, 4, and 24 h after surgery in group B were significantly lower than in group A (all P < 0.05). There were no differences in the adverse events between the 2 groups.We found that the pharmacokinetic model-based dosing scheme resulted in lower opioid requirements, lower pain scores, and no significant adverse events in the postanesthesia care unit following robot-assisted laparoscopic prostatectomy in comparison with conventional dosing regimen.     

Randomized Phase II study of two opposite administration sequences of irinotecan and cisplatin in patients with advanced nonsmall cell lung carcinoma

BACKGROUND: Combined chemotherapy with irinotecan and cisplatin (IP) is active in patients with nonsmall cell lung carcinoma (NSCLC). However, the optimal administration schedule needs to be defined to maximize its synergic effect. The authors evaluated the efficacy, toxicity, and pharmacokinetics (PK) of IP chemotherapy given on two administration sequences in chemotherapy-naive patients with NSCLC. METHODS: Eighty eligible patients were assigned randomly to receive 1 of 2 irinotecan and cisplatin administration sequences on Day 1: irinotecan followed by cisplatin (I-P) (n = 39 patients) or cisplatin followed by irinotecan (P-I) (n = 41 patients). Treatment was comprised of irinotecan at a dose of 80 mg/m(2) intravenously on Days 1 and 8 and cisplatin at a dose of 60 mg/m(2) intravenously on Day 1 of a 21-day cycle for a maximum of 6 cycles. For PK analysis, serial plasma samples were obtained on Day 1 of the first cycle. RESULTS: In total, 77 patients were assessable for efficacy. The overall response rate was 47%, and there was a trend in favor of P-I (54%) compared with I-P (39%). In multivariate logistic regression analysis, the P-I sequence and female gender were found to be significant predictors of a better response (P = 0.047 and P = 0.011, respectively). Overall toxicity profiles and PK parameters were similar in both arms. CONCLUSIONS: IP chemotherapy showed promising activity with a favorable 1-year survival rate. For future clinical use, the authors recommend administering cisplatin first and then irinotecan, because that sequence was associated with a higher response rate.     

Comparison of radiological and clinical results of balloon kyphoplasty according to anterior height loss in the osteoporotic vertebral fracture

Background context

Percutaneous kyphoplasty is effective for pain reduction and vertebral height restoration in patients with osteoporotic vertebral fractures. However, in cases of severely collapsed fractures involving the loss of more than 70% of the vertebral height, kyphoplasty is technically difficult to perform and the outcomes remain unknown.

Purpose

To compare the vertebral height restoration rate, kyphotic angle, and clinical results of patients who underwent kyphoplasty according to the degree of anterior vertebral height loss. In addition, to determine the feasibility and effects of kyphoplasty on severely collapsed osteoporotic vertebral fractures.

Study design/setting

A retrospective study.

Patient sample

A total of 129 patients (145 vertebrae) who underwent kyphoplasty for osteoporotic painful vertebral fracture and followed up for more than 1 year between September 2005 and August 2012 were recruited for the analysis.

Outcome measures

The patients' kyphotic angle, anterior vertebral height, and anterior vertebral height restoration ratio 1 year after surgery were compared. Pre- and postoperative pain around the fractured vertebra and the radiological and clinical results according to bone mineral density (BMD) were also compared.

Methods

Patients were divided into three groups for comparison, according to radiographic findings. Patients with an anterior height compression ratio more than 70% at the time of fracture comprised Group I, patients with a compression ratio of 50–70% comprised Group II, and those with a compression ratio of 30–50% comprised Group III.

Results

Group I showed a greater extent of anterior height restoration immediately after surgery compared with the other groups, which noticeably decreased over time. All three groups showed significant restoration of the anterior vertebral height between pre- and postoperative values. The anterior vertebral height 1 year after surgery did not differ between Group I and Group II but was significantly higher in Group III. There was no correlation between the BMD and restoration or decrease of anterior vertebral height over time. Pain around the fractured vertebra significantly decreased in all groups immediately and 1 year after surgery compared with preoperative levels, although the pain level 1 year after surgery did not differ significantly between the groups.

Conclusions

In patients with an anterior vertebral compression ratio more than 70% because of osteoporotic vertebral fracture, although the anterior height and kyphotic angle were significantly lower than those of patients with an anterior vertebral compression ratio of 30% to 50%, kyphoplasty significantly improved the degree of pain, restored the anterior vertebral height, and maintained the kyphotic angle. Therefore, kyphoplasty can be a useful approach in patients with an anterior vertebral compression ratio more than 70%.