Lutetium oxodotreotide (177Lu-Dotatate) for the treatment of unresectable or metastatic progressive gastroenteropancreatic neuroendocrine tumors: a cost-effectiveness analysis for Scotland.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogenous group of tumors. Findings from the phase III NETTER-1 trial showed that treatment of unresectable/metastatic progressive gastrointestinal (GI) NETs with 177Lu-Dotatate resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with best supportive care (BSC) with high dose octreotide long-acting repeatable (LAR) 60 mg. A health economic analysis was performed using input data from clinical studies and data derived from an indirect comparison to determine the cost-effectiveness of 177Lu-Dotatate in the treatment of GI-NETs and pancreatic NETs (P-NETs) in Scotland. METHODS: Cost-effectiveness analysis was performed from the payer perspective using a three-state partitioned survival model. In the base case 177Lu-Dotatate was compared with BSC in gastrointestinal (GI)-NETs using clinical data from the NETTER-1 trial. A secondary analysis comparing 177Lu-Dotatate with BSC, everolimus or sunitinib in patients with P-NETs was also performed using hazard ratios inferred from indirect comparisons. The base case analysis was performed over a 20-year time horizon with an annual discount rate of 3.5% for both costs and clinical outcomes. RESULTS: For unresectable/metastatic progressive GI-NETs treatment with 177Lu-Dotatate led to a gain in quality-adjusted life expectancy of 1.33 quality-adjusted life years (QALYs) compared with BSC due to extended PFS and OS. Mean total lifetime costs were GBP 35,701 higher with 177Lu-Dotatate, leading to an incremental cost-effectiveness ratio (ICER) of GBP 26,830 per QALY gained. In analyses in patients with P-NETs 177Lu-Dotatate was associated with ICERs below GBP 30,000 per QALY gained in comparisons with BSC, sunitinib and everolimus. CONCLUSIONS: Cost-effectiveness analyses demonstrated that, in Scotland, from the payer perspective, 177Lu-Dotatate at the set acquisition cost is a cost-effective treatment option for patients with unresectable or metastatic progressive GI-NETs or P-NETs.

Pharmacokinetics of ibafloxacin following intravenous and oral administration to healthy Beagle dogs.

The pharmacokinetics of ibafloxacin, a new veterinary fluoroquinolone antimicrobial agent, was studied following intravenous (i.v.) and oral administration to healthy dogs. The mean absolute bioavailability of ibafloxacin after oral doses of 7.5, 15 and 30 mg/kg ranged from 69 to 81%, indicating that ibafloxacin was well absorbed by dogs. Ibafloxacin was also absorbed rapidly [time of maximum concentration (t(max)) 1.5 h], reaching a mean maximum concentration (C(max)) of 6 microg/mL at 15 mg/kg, well distributed in the body [large volume of distribution at steady state (V(ss)) and V(area) of 1.1 L/kg and 4 L/kg, respectively], and exhibited an elimination half-life of 5.2 h and a low total body clearance (8.7 mL/min/kg). Both C(max) and area under the concentration-time curve (AUC) showed dose proportionality over the dose range tested (7.5-30 mg/kg). The pharmacokinetics of ibafloxacin was similar following single and repeated dosage regimens, implying no significant accumulation in plasma. Food promoted the absorption of ibafloxacin by increasing C(max) and AUC, but did not change t(max). High amounts of the metabolites, mainly 8-hydroxy- and, 7-hydroxy-ibafloxacin were excreted in urine and faeces, either unchanged or as glucuronide conjugates. Following oral administration of 15 mg ibafloxacin/kg, the total recovery of ibafloxacin, its metabolites and conjugates in urine and faeces was 61.9-99.9% of the dose within 48 h.

The effect of nimodipine monotherapy and combined treatment with ketamine and lignocaine in aneurysmal subarachnoid haemorrhage.

The clinical effects of nimodipine monotherapy were compared with the effects of nimodipine combined with ketamine and lignocaine (combination therapy) in a single-centre, one investigator, open study in patients with proven aneurysmal subarachnoid haemorrhage (aSAH). After clipping of the aneurysm, nimodipine was administered intravenously until day 5-7 after clipping. Thereafter the intravenous nimodipine was substituted by oral doses of nimodipine. These were decreased gradually and then discontinued within the following 6 days. For combination therapy, nimodipine was given together with both a bolus injection of 1 microgram/kg ketamine followed by an infusion of the drug at a rate of 3 micrograms/kg/min and a bolus injection of 1.5 mg/kg lignocaine followed by an infusion of the drug at a rate of 12 micrograms/kg/min. During the study period, 173 patients were admitted to the hospital with subarachnoid haemorrhage (SAH). Of these patients, 115 with a proven aneurysm were operated on and evaluated: 66 patients received nimodipine monotherapy and 49 were given nimodipine combined with ketamine and lignocaine. These subgroups were comparable in terms of the baseline characteristics (age, Hunt and Hess score). The (baseline corrected) Hunt and Hess scores after surgery and a 0-5 clinical outcome score were applied as indices for clinical effects. Patients receiving nimodipine monotherapy and combined therapy showed a significant clinical improvement compared to baseline (P = 0.001 and P = 0.006, respectively). The beneficial effect of nimodipine monotherapy is in line with previous double-blind, placebo-controlled studies. Although nimodipine monotherapy seems to be more effective than combined treatment, this was not statistically significant. Our data indicate that combined treatment with ketamine and lignocaine is not more effective than nimodipine monotherapy in patients with mild aSAH, but this does not rule out an effect in severe cases. There was no indication of a pharmacodynamic interaction between nimodipine and co-medication. No serious or clinically relevant adverse reactions were noted during the study.

No pharmacokinetic or pharmacodynamic interaction between theophylline and the leukotriene biosynthesis inhibitor BAY x 1005.

An open, randomized, three-period crossover study was conducted to compare the steady-state pharmacokinetics, pharmacodynamics, and tolerability of concomitant administration of BAY x 1005 and theophylline in 12 healthy volunteers. BAY x 1005 (250 mg twice daily; treatment A) and theophylline (400 mg twice daily; treatment B), were administered alone and concomitantly (treatment C) for 6 days with a final morning dose on day 7. The treatments were separated by washout periods of at least 5 days. Pharmacokinetic parameters were derived from concentrations of BAY x 1005 and theophylline as measured by high-performance liquid chromatography in plasma collected before the morning dose on days 5 and 6 and at various times on day 7 of each period until 24 hours after drug administration. Adverse events, vital signs, electrocardiograms, and clinical laboratory studies were monitored as safety parameters. Levels of leukotriene B4 (LTB4) were assessed in plasma collected on days 1 and 7. The treatments were well tolerated by all participants. The ratios of maximum concentration (Cmax) and area under the concentration-time curve for one 12-hour dosing interval (AUC tau) for treatment C versus B for theophylline on day 7 was 98% for both parameters. For BAY x 1005, the ratios of treatment C versus treatment A were 94% for Cmax and 101% for AUC tau. Plasma LTB4 remained virtually unchanged during either treatment. Steady-state concentrations of theophylline were not affected by concomitant BAY x 1005 intake, and addition of theophylline had no clinically relevant effect on steady-state plasma concentrations of BAY x 1005. The combination of theophylline and BAY x 1005 did not lead to a change in nature, intensity, or frequency of adverse events.

A comparative study of the steady-state pharmacokinetics of immediate-release and controlled-release diltiazem tablets.

We have studied the controlled-release properties and relative systemic availabilities of two dosages of the same controlled-release (CR) diltiazem tablet formulation by comparing them at steady state with those of an immediate-release formulation. We measured 24-hour plasma concentration profiles during 4-day treatments with diltiazem 90 mg CR tablet bd diltiazem 120 mg CR tablet bd, and conventional diltiazem 60 mg immediate-release (IR) tablet tid. The study had a randomized, three-way crossover design. Twelve healthy men (38-52 y) participated. Trough plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the last morning dose on day 4 of each period. The following steady-state pharmacokinetic values were calculated: the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), the time interval during which the plasma concentration exceeded 75% of Cmax (t75), the area under the plasma concentration-time curve (AUC72-96), the peak-to-trough fluctuation (PTF), and the area-under-the-curve fluctuation (AUCF). Steady state was achieved on day 3. The pharmacokinetics were comparable. For diltiazem CR 90 mg and diltiazem CR 120 mg, AUC84-96 (night) was approximately 75% of AUC72-84 (daytime). The diltiazem plasma concentration increased slowly from about 6 h after the evening dose of both CR tablets, resulting in relatively high plasma concentrations in the early morning hours. Only during treatment with diltiazem CR 120 mg were the plasma concentrations of diltiazem maintained above the minimum therapeutic plasma concentration of 50 micrograms.l-1 throughout the full 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Human pharmacokinetics of orally administered (24 R)-hydroxycalcidiol.

To gain an insight in the regulation of (24R)-hydroxycalcidiol, we studied the pharmacokinetics of orally administered (24R)-hydroxycalcidiol in 6 healthy subjects without calcium supplementation, in 4 healthy subjects with calcium supplementation and in 6 patients with primary hyperparathyroidism. Various quantities related to calcium and vitamin D metabolism were also monitored. In the healthy subjects without calcium supplementation, the basal (24R)-hydroxycalcidiol concentration (Cb) in serum was 2.4 +/- 0.8 nmol/l (mean +/- SD, n = 5), the terminal serum half-time (t 1/2) 7.2 +/- 1.4 days, the production rate 0.05 +/- 0.01 nmol/kg.day, and the production rate/[calcidiol] ratio (1.5 +/- 0.4 x 10(-3) l/kg.day). In the healthy subjects studied, the serum concentration vs time curves exhibited a second maximum after administration, possibly due to binding by intestinal cells or (partial) uptake by the lymph system. In the calcium-supplemented healthy subjects, the pharmacokinetic quantities were not significantly different while the area under the serum concentration-time curve and the estimated bioavailability were significantly decreased. Basal concentration (Cb), production rate and the production rate/[calcidiol] ratio were significantly lower in patients with primary hyperparathyroidism but t 1/2 was unchanged. Exogenous (24R)-hydroxycalcidiol had no clear effect on calcium and vitamin D metabolism. In conclusion, a) exogenous (24R)-hydroxycalcidiol has no clear effect on calcium and vitamin D metabolism, b) clearance and production rate of (24R)-hydroxycalcidiol are not affected by calcium supplementation, c) bioavailability is lower in the calcium-supplemented state, d) basal concentration (Cb) and production rate are significantly decreased in patients with hyperparathyroidism.

Calcium supplementation reduces vertebral bone loss in perimenopausal women: a controlled trial in 248 women between 46 and 55 years of age.

To study the effect of calcium supplementation on perimenopausal bone loss, 295 women were randomized into a control group and 2 supplementation groups receiving, respectively, 1000 and 2000 mg elemental calcium/day for a period of 2 yr. We observed a significant decrease in lumbar bone loss in relation to the calcium supplementation (mean loss after 2 yr of 3.5% in the control group vs. 1.3% and 0.7% in the 1000 and 2000 mg groups, respectively), a significant increase in urinary calcium excretion, and a significant decrease in the urinary hydroxyproline/creatine ratio, serum alkaline phosphatase, osteocalcin, and 1,25-dihydroxyvitamin D. The effect of calcium supplementation on lumbar bone loss was significant in the first year of supplementation, but not in the second. However, the urinary hydroxyproline/creatinine ratio and the serum alkaline phosphatase level remained significantly decreased in the treatment groups at the end of the study; this was not the case for serum osteocalcin. Calcium supplementation did not have a significant effect on metacarpal cortical bone loss. The difference in biochemical parameters between the 2 supplementation groups was small. No significant interaction was observed between the menopausal status of the subjects and the effect of calcium supplementation. We conclude that calcium supplementation retards lumbar bone loss in the first year of calcium supplementation by reducing bone turnover. However, the effect on lumbar bone loss over a longer time span is still uncertain.

Short-term effects of Org OD 14 and 17 beta-oestradiol on bone and lipid metabolism in early post-menopausal women.

The effects of 8 weeks of daily oral treatment with 1 mg 17 beta-oestradiol (E2), 2.5 mg Org OD 14 [7 alpha, 17 alpha)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one) , a steroid with weak androgenic, weak oestrogenic and weak progestational activity, or placebo on calcium and lipid metabolism were compared in 21 healthy, early post-menopausal women in a randomised double-blind study. The treatment period was followed by a treatment-free period of 8 weeks to study the reversibility of drug-induced effects. The results show that both E2 and Org OD 14 reduce bone resorption, as indicated by the decreases in the urinary hydroxyproline/creatinine and calcium/creatinine ratios in 2-h fasting urine. In contrast to E2, Org OD 14 did not reduce serum calcium levels. As regards lipid parameters, E2 reduced the concentration of serum cholesterol and Org OD 14 decreased serum levels of high-density-lipoprotein cholesterol and triglycerides. All these effects appeared to be reversible after cessation of treatment. It is concluded that both of these steroids reduce bone resorption in early post-menopausal women, but that their mechanisms of action are most likely different.

Effect of a single infusion of aminohydroxypropylidene on calcium and bone metabolism in healthy volunteers monitored during 2 months.

Recently, bisphosphonates have been used to prevent postmenopausal bone loss. As the effects of bisphosphonates on normal bone metabolism are unknown, 3-amino-1-hydroxypropylidene-1,1-diphosphonate (APD) was studied in healthy subjects. The effects of a single 20-mg APD infusion on biochemical parameters of calcium and bone metabolism were investigated during 2 months in 10 healthy male volunteers. This single moderate dose of APD reduced biochemical parameters of bone resorption during the time of follow-up. After 2 months, urinary hydroxyproline excretion was still below the basal level. The decreased serum calcium levels did not return to basal values. Biochemical parameters of bone formation, serum alkaline phosphatase and osteocalcin, showed a slight increase during the first month after stimulation of the parathyroids and a corresponding increase in serum 1,25-dihydroxyvitamin D. These formation parameters decreased thereafter, probably representing coupling between bone resorption and bone formation.

Reaction kinetics of cisplatin and its monoaquated species with the modulating agents (di)mesna and thiosulphate.

The reactive and rapidly excreted thiol mesna (2-mercaptoethane-sulphonate sodium) has the potential to reduce the dose-limiting nephrotoxicity of cisplatin by chemical neutralisation of the latter in the kidney. The reaction kinetics of cisplatin with mesna and its disulphide, dimesna, was studied at 37 degrees C in unbuffered 0.15 mol/l NaCl (pH 5.3) and in 0.15 mol/l NaCl buffered with 0.02 mol/l Hepes (pH 7.4). The reaction mixtures were analysed for intact cisplatin. In the presence of mesna or dimesna 0.5 mol/l as anticipated in urine for conditions of renal protection, the half-life (t1/2) of 0.2 mmol/l cisplatin was less than 6 min. t1/2 of 151 and 629 min were found in the presence of mesna and dimesna concentrations of 5 mmol/l and 3 mmol/l, respectively, anticipated in plasma under conditions of renal protection. Cis-diamminemonoaquamonochloroplatinum(II) 0.2 mmol/l reacted rapidly with 50 mmol thiosulphate and 0.5 mol/l (di)mesna (t1/2 less than or equal to 1 min). This platinum species also reacted rapidly with 2.6 mmol/l thiosulphate (t1/2 less than 1 min), a concentration reached in plasma for conditions under renal protection. Reaction of the monoaquated form of cisplatin proceeded slowly in the presence of dimesna or mesna concentrations (less than 5 mmol/l), as anticipated in plasma under renal protecting conditions. It is hypothesised that renal protection by the strong nucleophiles, thiosulphate, mesna and dimesna occurs rather by neutralisation of the aquated species in the lumen of the renal tubulus than by neutralisation of intact cisplatin, and that neutralisation of these species in plasma contributes significantly to the protecting effect.

Human pharmacokinetics of orally administered strontium.

Pharmacokinetics of orally administered SrCl2 (2.5 mmol) were studied in six healthy male volunteers. In the overall plasma concentration time (C-t) curves, two absorption phases were observed due to two dominant intestinal absorption loci. A method was devised to obtain separately the plasma C-t curves associated with each of the two absorption loci (curve 1 and curve 2). These curves and the overall plasma C-t curve were analyzed with a nonlinear estimation program (PCNONLIN). Pharmacokinetic parameters (mean +/- SD, n = 6) calculated from the overall curve were as follows: peak plasma concentration (Cmax) 3.55 +/- 1.22 micrograms/ml and area under the plasma C-t curve (AUC affinity) 9138 +/- 1930 micrograms.min/ml. The pharmacokinetic parameters calculated from curve 1 were as follows: terminal plasma elimination half-life time 47.3 +/- 7.9 hour, the plasma elimination half-life time of the preceding phase 5.2 +/- 3.3 hour, Cmax 1 3.09 +/- 0.95 micrograms/ml, the first-order absorption rate constant for absorption locus 1 (Ka,1) 5.7 +/- 1.2 * 10(-2) minute-1 and the time lag (tlag,1) 11.7 +/- 7.9 minute. In three of the subjects the pharmacokinetic parameters of absorption locus 2 could be evaluated: Ka,2 = 4.6 +/- 0.4 * 10(-2) minute-1, tlag,2 = 77.3 +/- 4.0 minute, tmax,2 = 153 +/- 16 minute, Cmax,2 = 0.9 +/- 0.4 micrograms/ml and AUC 2 affinity = 1204 +/- 565 micrograms. minute/ml. and AUC2 affinity = 0.14, indicating that 14% of the absorbed dose was absorbed via the second locus.(ABSTRACT TRUNCATED AT 250 WORDS)

Reaction kinetics of cisplatin and its monoaquated species with the (potential) renal protecting agents (di)mesna and thiosulfate. Estimation of the effect of protecting agents on the plasma and peritoneal AUCs of CDDP.

Using simple kinetic modelling, we estimated the effect of nucleophilic (renal) protecting agents (thiosulfate, mesna, diethyldithiocarbamate) on the half-life and the area under the concentration-time curve (AUC) of cis-diamminedichloroplatinum(II) (CDDP) in plasma and peritoneum. Our basic assumptions were that (a) under non-protecting conditions, the elimination of intact CDDP from plasma and peritoneum is a first-order process determined by the elimination-rate constant (k), and (b) under conditions of renal protection the elimination of CDDP is a first-order process determined by kCDDP,P = kCDDP+kN.[N], with kCDDP,P representing kCDDP under conditions of protection; kN, the second-order rate constant for direct interaction of the protecting nucleophile (N) and CDDP; and [N], the (steady-state) concentration of N. Half-lives under conditions of protection were 0.693/kCDDP,P. AUCs were obtained by integration of the first-order equations. The inactivation-indicating parameter was defined as being the ratio of the AUC under protecting conditions to the AUC under non-protecting conditions (Rinact). Rinact is approximately given by kCDDP/kCDDP,P. For renal protection with i.v. thiosulfate (TS, 2 g m-2h), the estimates of Rinact were 0.61 in plasma and 0.7 in the peritoneal cavity for i.p. injected CDDP and 0.87 in plasma for i.v. CDDP, indicating inactivation of CDDP under such conditions. Estimates of Rinact were 0.84 or 0.96 in plasma and 0.87 in the peritoneal cavity for supposed conditions of renal protection by systemic mesna (4.4 g m-2 h), suggesting only minor inactivation of i.p. or i.v. injected CDDP under such conditions. Under reported conditions of protection achieved with 4.4 g m-2 h systemic diethyldithiocarbamate (DDTC). Rinact was greater than 0.65 or 0.87 in plasma and greater than 0.75 in the peritoneal cavity for i.p. or i.v. injected CDDP, respectively. Thus, DDTC inactivates CDDP to a comparable or lesser extent than does TS.

Quantification of strontium in plasma and urine with flameless atomic absorption spectrometry.

This analytical method for determination of Sr in plasma and urine involves flameless atomic absorption spectrophotometry (FAAS). Drying, charring, and atomization were optimized with respect to temperature, temperature ramp, and duration for Sr in dilute HNO3 and Sr in plasma diluted 20-fold with dilute HNO3. Calibration curves (r greater than 0.995) were linear in the concentration range 5-250 micrograms/L for Sr in various media, with intercepts negligibly small except for the calibration curves in 1:1-diluted plasma and undiluted urine. The estimated detection limits for Sr in 20-fold-diluted plasma and 50-fold-diluted urine were 2 and 3 micrograms/L, respectively. Endogenous Sr in plasma and urine was estimated at 16 (SD 8) micrograms/L and 158 (SD 26) micrograms/L (n = 6), respectively. Intra- and interassay CVs were 9.1% and 5.3% for 20-fold-diluted plasma at a Sr concentration of 25 micrograms/L, and 6.9% and 4.8% at a concentration of 250 micrograms/L. The respective CVs were 8.2% and 1.2% for 50-fold-diluted urine at the low concentration, and 4.0% and 4.6% at the high concentration. In a pharmacokinetic pilot study of 2.5 mmol of Sr orally administered to a healthy volunteer, the peak plasma concentration of Sr, 4.4 mg/L, decayed bi-exponentially [t1/2, alpha = 24 h, t1/2, beta = 77 h]; the estimated first-order absorption rate constant was 0.005 min-1; and the observed decay (day 0-6) of the urinary Sr/creatinine ratio closely paralleled the plasma decay [t1/2 = 70 h].

Specific cation effect in the reaction of nitroprusside with cysteine, acetophenone and sulfite (Legal and Boedeker reaction).

The colour formation of cysteine (I), acetophenone (II) and sulfite (III) with the sodium and tetrabutylammonium (TBA) salt of nitroprusside (NP2-) in aqueous solution was studied. The intensity of colour formation depends strongly on the nature and concentration of the cations and increases in the order TBA less than Li less than Na less than K less than Rb less than Cs (in case of cysteine TBA and Li are interchanged). This specific cation effect was known for the Boedeker reaction (III) and is now also demonstrated for the Legal reaction (I and II). The adduct formation between NP2- and I to III is based on an anion-anion interaction. The role of the cation is to reduce the Coulombic repulsion between the reactants by ion-pair formation. The efficiency of ion-pair formation corresponds with the order given before except for TBA, which behaves divergently.

Nitroprusside, antihypertensive drug and analytical reagent. Review of (photo)stability, pharmacology and analytical properties.

A review of physical, chemical, analytical and pharmacological properties of nitroprusside is presented. In view of the pharmaceutical applications of nitroprusside special attention is given to the discussion of the (photo)degradation, the stability of the pharmaceutical formulations, the application as a reagent in pharmaceutical analysis and the redox behaviour.