Indirect bioequivalence assessment using network meta-analyses.

AIMS: For market approval, new drug formulations (test) must demonstrate bioequivalence (BE) to at least one approved formulation (reference). If several formulations of a drug are already on the market, one might have to show BE to more than one reference formulation. Similarly, if several test formulations have shown BE to a reference formulation, it will be of interest whether the test formulations are bioequivalent to each other. METHODS: An enhanced statistical model to assess BE indirectly through a network meta-analysis is provided. Statistical properties of a parallel and a bridging approach are derived, in particular the relative statistical efficiency of the two approaches. The analysis is illustrated using individual subject data from two 3×3 crossover trials of metformin formulations, which have one of the formulations in common. RESULTS: The parallel estimate of relative bioavailability is confounded with between-trial differences, while the bridging estimate is not. The standard errors of the formulation differences using the bridging approach are smaller than the standard errors using the parallel approach if the within-subject correlation in each trial of the network is larger than 0.5. This is the condition for a crossover trial to be more efficient than a parallel trial, and thus is usually fulfilled in pharmacokinetic crossover trials. CONCLUSIONS: Indirect BE assessment offers the opportunity to efficiently determine the relative bioavailability of drug formulations that have not been studied in the same randomized BE trial. The methodology developed here allows estimating formulation differences across a larger network.

Improved non-invasive T-Staging in non-small cell lung cancer by integrated 18F-FDG PET/CT.

AIM: In this prospective study, reliability of integrated (18)F-FDG PET/CT for staging of NSCLC was evaluated and compared to MDCT or PET alone. PATIENTS, METHODS: 240 patients (pts) with suspected NSCLC were examined using PET/CT. Of those patients 112 underwent surgery comprising 80 patients with NSCLC (T1 n = 26, T2 n = 37, T3 n = 11, T4 n = 6). Imaging modalities were evaluated independently. RESULTS: MDCT, PET and PET/CT diagnosed the correct T-stage in 40/80 pts (50%; CI: 0.39-0.61), 40/80 pts (50%; CI: 0.39-0.61) and 51/80 pts (64%; CI: 0.52-0.74), respectively, whereas equivocal T-stage was found in 15/80 pts (19%; CI: 0.11-0.19), 12/80 pts (15%; CI: 0.08-0.25) and 4/80 pts (5%; CI: 0.01-0.12), respectively. With PET/CT, T-stage was more frequently correct compared to MDCT (p = 0.003) or PET (p = 0.019). Pooling stages T1/T2, T-stage was correctly diagnosed with MDCT, PET and PET/CT in 54/80 pts (68%; CI: 0.56-0.78), 56/80 pts (70%; CI: 0.59-0.80) and 65/80 pts (81%; CI: 0.71-0.89). T3 stage was most difficult to diagnose. T3 tumors were correctly diagnosed with MDCT in 2/11 pts (18%; CI: 0.02-0.52) versus 0/11 pts (0%; CI: 0.00-0.28) with PET and 5/11 pts (45%; CI: 0.17-0.77) with PET/CT. In all imaging modalities, there were no equivocal findings for T4 tumors. Of these, MDCT found the correct tumor stage in 4/6 pts (67%; CI: 0.22-0.95), PET in 3/6 pts (50%; CI: 0.12-0.88) and PET/CT in 5/6 pts (83%; CI: 0.36-0.99). CONCLUSION: Integrated PET/CT was significantly more accurate for T-staging of NSCLC compared to MDCT or PET alone. The advantages of PET/CT are especially pronounced combining T1- and T2-stage as well as in advanced tumors.

Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin.

This article reports the clinical investigation of a probe drug cocktail containing substrates of key drug transporters. Single oral doses of 0.25 mg digoxin (P-gp), 5 mg furosemide (OAT1 and OAT3), 500 mg metformin (OCT2, MATE1, and MATE2-K), and 10 mg rosuvastatin (OATP1B1, OATP1B3, and BCRP) were administered separately or as a cocktail in a randomized six-period crossover trial in 24 healthy male volunteers. As a cocktail, relative bioavailabilities of digoxin and metformin and furosemide AUC0-tz were similar to separate dosing. However, when administered as a cocktail the Cmax of furosemide was 19.1% lower and the Cmax and AUC0-tz of rosuvastatin were 38.6% and 43.4% higher, respectively. In addition, the effects of increased doses of metformin or furosemide on the cocktail were investigated in 11 and 12 subjects, respectively. The cocktail explored in this trial has the potential to be used for the in vivo screening of transporter-mediated drug-drug interactions. © 2016 American Society for Clinical Pharmacology and Therapeutics.

[The indications and the efficiency of x-ray therapy of the eyelid tumours (author's transl)]. / Indikation und Resultate der Radiotherapie der Augenlid-und Augenwinkeltumoren.

A short introduction deals with the frequency, the distribution and the histology of eyelid-tumors. Then the indication, the technics and the efficiency of X-ray therapy is discussed. Only malignomes of the early stage of TU I and TU II that are made sure by histological research may be treated by an experienced X-ray therapist. It is pointed to the importance of cooperation and the common planning between ophthalmic-surgical and X-ray therapeutics centers and the oculist. Observing the correct indication and technics we reached 97% of 5 years healing by X-ray therapy with our material of malign tumours of the eyelid in the early stage of TU I and TU II.

[New aspects in the treatment of breast cancer (author's transl)]. / Die Problematik der Therapie des Mammakarzinoms in neuerer Sicht

The specific treatment of primary breast carcinoma in the future may depend on viral genes in the development of antiviral substances, or a specific chemotherapeutic method. In this manner the turnover rate of the RNS virus is successfully inhibited (as the preceding communicated observations about the probably produced inhibition effect of rifampicin derivates of streptovarizin complexes). Prophylactically, by familiar breast cancer, breast feeding must be prohibited so that a supposed virus factor would not transfer with the milk. So far we hope that a supposed virus diagnosis of the primary tumor leads to decreased surgical interventions (tumorectomy, radical mastectomy), and technical as well as high energy postradiotherapy. This would not only give a smaller psychologic shock to the patient (small operation trauma) but would also decrease the complications (arm edema, movement restriction). This opinion now appears to effect international thinking after radical and subradical surgery have not given better results. For the late stage there is modern chemotherapy, combined with proper radiotherapy treatment of painful skeletal metastases, eventually also brain metastases which can now be successfully irradiated. Whether better late results are obtained by the early chemotherapy as well as the improvement of the immunity reaction quickly after sugical intervention (modified radical mastectomy) will be seen in the near future.