Evaluation of various static and dynamic modeling methods to predict clinical CYP3A induction using in vitro CYP3A4 mRNA induction data.

Several drug-drug interaction (DDI) prediction models were evaluated for their ability to identify drugs with cytochrome P450 (CYP)3A induction liability based on in vitro mRNA data. The drug interaction magnitudes of CYP3A substrates from 28 clinical trials were predicted using (i) correlation approaches (ratio of the in vivo peak plasma concentration (Cmax) to in vitro half-maximal effective concentration (EC50); and relative induction score), (ii) a basic static model (calculated R3 value), (iii) a mechanistic static model (net effect), and (iv) mechanistic dynamic (physiologically based pharmacokinetic) modeling. All models performed with high fidelity and predicted few false negatives or false positives. The correlation approaches and basic static model resulted in no false negatives when total Cmax was incorporated; these models may be sufficient to conservatively identify clinical CYP3A induction liability. Mechanistic models that include CYP inactivation in addition to induction resulted in DDI predictions with less accuracy, likely due to an overprediction of the inactivation effect.

Prediction of Phase I single-dose pharmacokinetics using recombinant cytochromes P450 and physiologically based modelling.

1. Ten compounds from the Merck Research Laboratories pipeline were selected to evaluate the utility of using intrinsic clearance derived from recombinantly expressed cytochromes P450 (CYP) and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics using simCYP. The compounds selected were anticipated to be eliminated predominantly by P450 metabolism. 2. There was a reasonable agreement between the predicted and actual clinical exposure with 80% of the predicted exposures being within three-fold of the observed values. Furthermore, prediction of C(t) (plasma concentration at a specified time point) and T(max) were acceptable with greater than or equal to 70% of the predicted data being within three-fold of the observed values. However, prediction of C(max) was unreliable and may have been due to error in predicting the time-dependent change in volume of distribution and/or error in estimating absorption rate. 3. Although it is acknowledged that research is needed to improve predictive performance, the data presented are supportive of using recombinant P450 intrinsic clearance and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics for compounds eliminated by P450 metabolism.

Boron neutron capture therapy of brain tumors: investigation of urinary metabolites and oxidation products of sodium borocaptate by electrospray ionization mass spectrometry.

Boron neutron capture therapy (BNCT) is based on a nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low energy neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. The purpose of the present study was to determine what urinary metabolites, if any, could be detected in patients with brain tumors who were given sodium borocaptate (BSH), a drug that has been used clinically for BNCT. BSH was infused intravenously over a 1-h time period at doses of 26.5, 44.1, or 88.2 mg/kg of body weight to patients with high-grade brain tumors. Electrospray ionization mass spectrometry has been used to investigate possible urinary metabolites of BSH. Chemical and instrument conditions were established to detect BSH and its possible metabolites in both positive and negative electrospray ionization modes. Using this methodology, boronated ions were found in patients' urine samples that appeared to be consistent with the following chemical structures: BSH sulfenic acid (BSOH), BSH sulfinic acid (BSO(2)H), BSH disulfide (BSSB), BSH thiosulfinate (BSOSB), and a BSH-S-cysteine conjugate (BSH-CYS). Although BSH has been used clinically for BNCT since the late 1960s, this is the first report of specific biotransformation products following administration to patients. Further studies will be required to determine both the biological significance of these metabolites and whether any of these accumulate in significant amounts in brain tumors.

Boron neutron capture therapy of brain tumors: biodistribution, pharmacokinetics, and radiation dosimetry sodium borocaptate in patients with gliomas.

OBJECTIVE: The purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODS: BSH (non-10B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTS: Blood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 microg/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean +/- standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1+/-5.8 and 17.3+/-10.1 microg/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 microg/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6+/-5.1 and 5.5+/-3.9 microg/g and the tumor/normal brain tissue ratios were3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 microg/ml at 2 hours to 63 microg/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 microg/g, respectively, during the 3- to 7-hour sampling period. CONCLUSION: When tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.

The effects of betaxolol hydrochloride ophthalmic solution on intraocular pressures during transient microgravity.

BACKGROUND: Intraocular pressure (IOP) has been found to increase during microgravity. After peaking in the first few hours of orbital flight, IOP slowly decreases to a level that is slightly elevated above baseline IOP's. These modest elevations in IOP do not require treatment. Just as in 1-G, a clinically significant elevation of IOP that occurred during spaceflight would require treatment. We are not aware of previous studies of the efficacy of IOP lowering agents under conditions of microgravity. METHODS: This double-masked, placebo-controlled study measured the IOP's of 11 adult subjects (22 eyes) at baseline, preflight, and zero-gravity aboard the NASA KC-135 aircraft, and postflight. One eye of each of the subjects was treated with betaxolol hydrochloride ophthalmic solution 0.5%, while the contralateral eye was treated with normal saline placebo, for 7 d prior to parabolic flight. IOP's were measured by the Tono-Pen 2, a gravity independent tonometer. RESULTS: A modest, but statistically significant reduction of 2.4 mmHg in mean IOP was noted in betaxolol treated eyes at the time of preflight measurement. During zero-G, the mean IOP's of both betaxolol treated eyes and placebo treated eyes increased approximately 20% over preflight levels. Postflight IOP's were similar to preflight IOP's. CONCLUSIONS: The effect of betaxolol on the IOP of eyes treated with for 1 wk prior to exposure to microgravity was statistically significant, but may lack clinical significance in normal eyes. Further research needs to be done to determine the efficacy during microgravity of betaxolol and other agents, in subjects who have upper normal to slightly elevated IOP's at 1 G.

Stability of vision during space flight in an astronaut with bilateral intraocular lenses.

PURPOSE: To report excellent and stable vision in an astronaut during space flight after bilateral cataract surgery with intraocular lenses. METHODS: A 60-year-old physician mission specialist astronaut developed cataracts and underwent phacoemulsification with insertion of one-piece polymethylmethacrylate intraocular lenses that had 6-mm optics bilaterally. Several months later, he flew on a space shuttle mission. Ocular examinations were performed before and after the mission, and the patient was questioned about visual changes during flight. RESULTS: Ocular examinations demonstrated stable bilateral posterior chamber intraocular lenses. Our subject reported excellent vision during liftoff, 18 days of microgravity, changes in cabin pressure, and reentry. CONCLUSION: Results suggest that intraocular lenses are safe, effective, and well tolerated during space flight.

Intraocular pressure and retinal vascular changes during transient exposure to microgravity.

We measured intraocular pressures and retinal vascular diameters from 11 subjects during 20 seconds of microgravity produced by parabolic flight on board a KC-135 aircraft. Intraocular pressures increased 58% during parabolic flight compared to baseline values (19 +/- 1 mm Hg vs 12 +/- 1 mm Hg, respectively; P < .001). A 4% reduction in the caliber of retinal arteries was also noted during microgravity, but this change did not achieve statistical significance (7.8 +/- 0.3 pixels at zerogravity vs 8.1 +/- 0.3 pixels at 1g; P = .07). The increase in intraocular pressure and trend of arteries to constrict are thought to result from cephalad shifts in intravascular and extravascular body fluids as a result of the absence of the 1g hydrostatic gradient. The results of our study confirm that this fluid shift and its effects on the eye occur rapidly, within 20 seconds of exposure to microgravity.