Intravenous Dosing Regimens Research Articles

Pharmacokinetics, urinary excretion and plasma protein binding of pralidoxime in goats

The blood levels of cholinesterase reactivator pralidoxime (2-PAM) were determined in goats following single dose intravenous administration @ 30 mg/kg body weight injected as 6% freshly prepared solution. Blood and urine samples were collected at different predetermined time intervals and 2-PAM was analysed by spectrometric method with the minimum detection of 1.0 μg ml −1. The peak plasma concentration was 49.52 ± 3.99 μg ml −1 at 2 min post administration which rapidly declined to 15.53 ± 2.11 μg ml −1 at 10 min. Thereafter, it gradually disappeared to 1.33 ± 0.41 μg ml −1 at 1.5 h. The pharmacokinetic parameters were determined by employing two-compartment open model. The t 1/2 α , t 1/2 β , Vd area and Cl B were calculated to be 1.68 ± 0.35 min, 21.17 ± 1.65 min, 1277.95 ± 195.67 ml/kg and 41.17 ± 3.66 ml/kg/min, respectively. Approximately 52% of the total administered dose was eliminated in urine within 24 h. The plasma protein binding was estimated by equilibrium dialysis technique. The in vitro plasma protein binding of 2-PAM was 64.7%. Based on these data, a satisfactory intravenous dosage regimen of 2-PAM in goats would be 38 mg/kg body weight repeated at hourly intervals.

AXIS

Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data. Four intravenous dose regimens (total cumulative doses of 30-180 μg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch. Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions > 14-17 cm³. We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points.

Pharmacokinetics, urinary excretion and plasma protein binding of 2,3-butanedione monoxime in goats

Inhibition of acetylcholinesterase in the central and peripheral nervous system is the basic mechanism of action of organophosphate nerve agents. Of the several phosphorylated acetylcholinesterase reactivators available, 2,3-butanedione monoxime has been reported to successfully reactive acetylcholinesterase enzyme in central nervous system of domestic animals severely poisoned with organophosphorus insecticides. The blood levels of cholinesterase reactivator 2,3-butanedione monoxime (common name diacetyl monoxime; abbreviated as DAM) were determined in goats following single dose intravenous administration @ 30 mg/kg body weight injected as 6% solution. Blood and urine samples were collected at different predetermined time intervals and DAM was analysed by colorimetric method with the minimum detection of 1.0 μg ml −1. The pharmacokinetic parameters were determined by employing two-compartment open model. The t 1/2α, t 1/2β, Vd area and Cl B were calculated to be 6.02 ± 2.65 min, 103.3 ± 8.54 min, 548.86 ± 96.53 ml/kg and 3.64 ± 0.41 ml/kg/min, respectively. Approximately 10.44% of the total administered dose was eliminated in urine within 24 h. The plasma protein binding was estimated by equilibrium dialysis technique. The in vitro plasma protein binding of DAM was 54.4%. Based on these data, a satisfactory intravenous dosage regimen of DAM in goats would be 28 mg/kg body weight repeated at 6 h intervals.

Pharmacokinetics and pharmacodynamics of low doses of midazolam administered intravenously and orally to healthy volunteers

1. Midazolam, a short-acting benzodiazepine, has been considered a probe for estimating hepatic and intestinal cytochrome P450 (CYP) 3A activity in humans. The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of midazolam administered intravenously (i.v.) and orally (p.o.) at relatively low doses to healthy volunteers. 2. The present study was an open-label, single-sequence trial in three phases distinguished by differing doses of midazolam. Plasma concentrations of midazolam and its metabolites, as well as pharmacodynamic parameters, were measured simultaneously after administration of 5, 15 and 30 microg/kg, i.v., midazolam and 15, 50 and 100 microg/kg, p.o., midazolam. 3. The area under the concentration-time curve (AUC) of midazolam was significantly correlated with dose after both i.v. and oral administration (both P < 0.001). The AUC(0-6) of midazolam after oral administration was also well correlated with the area under the effect curve for peak saccadic velocity (PSV; P < 0.018), postural sway area (PSA; P < 0.069) and mental sedation as measured on a visual analogue scale (VAS; P < 0.054), but not for critical flicker fusion. 4. The present study has shown that the pharmacokinetics of midazolam at relatively low doses are linear for both intravenous and oral dosing regimens. In addition, PSV, PSA and VAS may be useful for the simultaneous evaluation of the pharmacokinetics and pharmacodynamics of midazolam at subtherapeutic doses.

Pharmacokinetics and Pharmacodynamics of a Bolus and Infusion of Cangrelor: A Direct, Parenteral P2Y12 Receptor Antagonist

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers. Twenty-two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens: a 15-microg/kg bolus followed by a 2-microg/kg/min infusion or a 30-microg/kg bolus followed by a 4-microg/kg/min infusion. The infusion is continued for 60 minutes, and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters. Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes. Moreover, extensive platelet inhibition is maintained throughout the infusion period with near-full recovery of platelet function within 60 to 90 minutes of terminating the infusion. The effect of high-dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate-induced P-selectin expression; how ever, no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function. Cangrelor administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function.

117: Magnesium sulfate (MgSO4) dose and timing, and umbilical cord Mg++ concentration: Relationship to cerebral palsy (CP)

To assess MgSO4 dose and timing (as actually used) and total umbilical cord blood Mg++ concentration in relationship to CP. Data are from a randomized clinical trial of MgSO4 to prevent CP among the offspring of women with anticipated preterm delivery from 24-31 weeks′ gestation. The planned dosing regimen was a 6-gm loading dose, 2 gm/hr infusion for up to 12 hrs, discontinuation if delivery not imminent, and re-treatment through 336 weeks′ gestation with the same regimen prior to delivery. We excluded infants with major congenital anomalies and performed logistic regression analyses adjusted for gestational age at birth. Of 2,056 children assessed for cerebral palsy, 1,311 (64%) underwent umbilical cord total Mg++ measurement. Median cord Mg++ (meq/L) was 2.6 (interquartile range [IQR] 1.7 −3.4) in the active group (n = 622) vs. 1.6 (IQR 1.4 −1.7) in the placebo (n = 689). Cord Mg++ was negatively but not significantly correlated with CP, adjusted OR 0.76, 95% CI 0.54-1.1. Among 986 MgSO4-allocated pregnancies (median dose 32.0 gm, IQR 29.0-45.1), dose and exposure were characterized as 1) any MgSO4 in last 3, 12, or 24 hrs before delivery; 2) total dose; and 3) duration in the same time intervals. In all of these exposure/dose analyses (n =10), receipt, dose, and duration of MgSO4 were not significantly related to CP risk; however, in all but one the association was in the negative direction (i.e., ↑ MgSO4, ↓ CP). The low (3.7 %) rate of CP among the children in the MgSO4-allocated pregnancies, and the 4.0% rate among those with a cord blood Mg++ measurement limited our statistical power. Our analyses do not support any specific modification of the intravenous MgSO4 dosing regimen that reduced the rate of cerebral palsy in our clinical trial.

Dosing Ketamine for Pediatric Procedural Sedation in the Emergency Department

To describe intravenous ketamine dosing regimens for children requiring brief procedural sedation. Time-concentration and sedation profiles were simulated in children (2, 6, and 12 years old) using published pediatric pharmacokinetic and pharmacodynamic parameter estimates. Single-dose, repeat-dosing, and infusion regimens to achieve sedation level of less than 2 (arouses slowly to consciousness, with sustained painful stimulus) for 15 minutes were investigated. A single bolus dose of 1.5 and 1.75, 2, and 2.125 mg/kg (for adult and 12-, 6-, and 2-year-olds, respectively) was required to achieve the desired sedation. Anticipated recovery would be slow, and a sedation level of 4 (drowsy, eyes open or closed but easily arouses to consciousness with verbal stimulus) was reached only after 70 minutes. The use of a smaller initial bolus with a subsequent half-dose "top-up" at 8 minutes achieves the same sedation level but with earlier recovery. A smaller initial dose of 0.25 and 0.275, 0.3, and 0.35 mg/kg followed by an infusion 2.5 and 2.75, 3, and 3.5 mg/kg per hour (for adult and 12-, 6-, and 2-year-olds, respectively) for 15 minutes gives a more even sedation level and rapid recovery (20 minutes to sedation level 4). Dosing increases with decreasing age. A large single dose is associated with deep sedation, possible adverse effects, and delayed recovery. Between-subjects variability is large, and dose should be tailored to clinical monitoring and requirement. Intermittent pain insult is better suited to a top-up technique, whereas continuous pain is better suited to an infusion technique.

Long-Term Protective Effects of Zoledronic Acid on Cancellous and Cortical Bone in the Ovariectomized Rat

Current bisphosphonate therapies effectively prevent bone loss in postmenopausal women. We studied the effect of a single intravenous dose of ZOL in ovariectomized rats. Protection from bone loss was dose dependent, lasting for up to 32 weeks, supporting the rationale for an annual intravenous dosing regimen of ZOL for treatment of postmenopausal osteoporosis. Once-yearly dosing with zoledronic acid (ZOL) 5 mg can increase BMD and reduce fracture rate in postmenopausal women with low BMD. The primary objective of this study was to determine the duration of bone protective effects of a single dose of ZOL in ovariectomized rats, an animal model of postmenopausal osteopenia. Secondary objectives were to determine the effects on bone turnover and mechanical properties. Female Wistar rats (10 per group) received single intravenous doses of ZOL 0.8, 4, 20, 100, or 500 microg/kg, alendronate 200 microg/kg, or isotonic saline 4 days before bilateral ovariectomy. Sham-operated controls were pretreated with saline. Mass and density of cancellous and cortical bone (pQCT) were measured at 4-wk intervals for 32 wk. Bone architecture (microCT), bone formation dynamics (fluorochrome label-based histomorphometry), and biomechanical strength in compression testing were also assessed at 32 wk. Ovariectomy-associated BMD loss was significantly attenuated for 32 wk by ZOL >or=4 microg/kg for total BMD, ZOL >or=20 microg/kg for cortical BMD, and ZOL >or=4 microg/kg for cancellous BMD (p < 0.01 versus ovariectomized controls). Alendronate 200 microg/kg was of equivalent potency to ZOL 20 microg/kg. Ovariectomy-associated decreases in trabecular architectural parameters were dose-dependently attenuated by ZOL. Alendronate 200 microg/kg was equivalent to ZOL 20 microg/kg. The bone resorption marker TRACP5b indicated transient suppression of elevated osteoclast activity by ZOL relative to OVX-rats even at the lowest dose of 0.8 microg/kg, whereas at 100-500 microg/kg, the effect was significant relative to the OVX control for the entire duration of the study of 32 wk. Bone formation parameters were not significantly affected by ZOL 20 microg/kg but were significantly reduced by ZOL 100-500 microg/kg. Alendronate 200 microg/kg was equivalent to ZOL 100 microg/kg. ZOL produced dose-related improvements in bone strength parameters after ovariectomy. Alendronate 200 microg/kg was of similar potency to ZOL 20 microg/kg. The duration and magnitude of the bone-protecting effect of a single intravenous dose of ZOL in ovariectomized rats is dose dependent and lasts for up to 32 wk. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. These data support the use of an annual intravenous ZOL dosing regimen for the treatment of osteoporosis.

Treatment of Paget's disease of bone: A survey of clinical practice in Australia

Consensus guidelines for the treatment of Paget's disease of bone have been published, but it is not known how closely these reflect clinical practice. We conducted a multi-centre, stratified, retrospective review of case notes of 531 subjects treated for Paget's disease of bone between 2000 and 2005 in 29 Australian centres. The subjects received 1072 courses of bisphosphonate treatment (pamidronate 363, alendronate 324, risedronate 208, tiludronate 103, zoledronic acid 69, and etidronate 5). The most recent treatment received was oral therapy in 57% of patients (alendronate 29%, risedronate 24%, and tiludronate 4%) and intravenous in 43% (pamidronate 33%, and zoledronic acid 10%). For oral bisphosphonates, the percentages of courses which were at the recommended dosage and duration were: alendronate 33%, risedronate 60% and tiludronate 29%. Pamidronate was administered in a wide range of dosing schedules, most commonly 60 mg every 3 months (18%), 6 months (17%) or annually (12%), whereas zoledronic acid was mainly given as a 4 mg infusion (98%) as a single dose (52%) or annually (19%). Most clinicians reported taking into account symptoms, plasma alkaline phosphatase activity and anatomical location of disease in determining the need for treatment. Patient preference, intolerance of oral therapy and compliance were ranked highest in determining the choice between oral and intravenous therapy. We conclude that oral and intravenous bisphosphonate dosing regimens are both commonly used to treat Paget's disease of bone in Australia. Only a minority of courses of oral bisphosphonate treatment are at the recommended dosage and duration, and there is a lack of consensus on regimens for intravenous treatment.

Disposition kinetics and urinary excretion of levofloxacin on concomitant administration with meloxicam in cross-bred calves

The disposition kinetics and urinary excretion study of levofloxacin was conducted in 5 male cross-bred calves following its single intravenous administration (4 mg kg −1) concurrently with meloxicam (0.5 mg kg −1). Levofloxacin was estimated by microbiological assay. The drug levels above MIC 90 in plasma, were detected up to 10 h. Disposition kinetic parameters were calculated by two-compartment open model. Rapid distribution of levofloxacin was evidenced by a small distribution half-life (0.13 ± 0.01 h) and high K 12/ K 21 ratio (2.21 ± 0.15). High ratio of AUC/MIC (90.2 ± 3.41) indicated good antibacterial activity of levofloxacin. The AUC, Vd area, elimination half-life, MRT and total body clearance were 9.02 ± 0.34 μg ml −1 h, 1.38 ± 0.05 l kg −1, 2.16 ± 0.08 h, 2.58 ± 0.11 h and 0.45 ± 0.02 l kg −1 h −1, respectively. About 38.4% of the administered dose of levofloxacin was excreted in urine within 24 h. A suitable intravenous dosage regimen for levofloxacin would be 1.8 mg kg −1 repeated at 8 h intervals when prescribed with meloxicam in calves.

A pharmacokinetic/pharmacodynamic mathematical model accurately describes the activity of voriconazole against Candida spp. in vitro

We developed a pharmacokinetic/pharmacodynamic (PK/PD) mathematical model that fits voriconazole time–kill data against Candida isolates in vitro and used the model to simulate the expected kill curves for typical intravenous and oral dosing regimens. A series of E max mathematical models were used to fit time–kill data for two isolates each of Candida albicans, Candida glabrata and Candida parapsilosis. PK parameters extracted from human data sets were used in the model to simulate kill curves for each isolate. Time–kill data were best fit by using an adapted sigmoidal E max model that corrected for delays in candidal growth and the onset of voriconazole activity, saturation of the number of Candida and the steepness of the concentration–response curve. The rates of maximal killing by voriconazole ( k max) were highly correlated with the growth rates ( k s) of the isolates (Pearson's correlation coefficient = 0.9861). Simulations using PK parameters derived from the human data sets showed fungistatic effects against each of the isolates. In conclusion, we demonstrated that the activity of voriconazole against Candida isolates can be accurately described using a mathematical model. In the future, it might be possible to devise optimal dosing regimens of voriconazole using the model and PK data collected in vivo.

Subacute Toxicity of Colistin Methanesulfonate in Rats: Comparison of Various Intravenous Dosage Regimens

The relative nephro- and neurotoxicity of colistin methanesulfonate (CMS) was investigated with rats during 7 days of intravenous administration in regimens mimicking twice- and once-daily dosing of a clinically relevant dose for humans. Histological examination revealed more-severe renal lesions with the regimen corresponding to once-daily dosing, indicating that the potential for renal toxicity may be greater with extended-interval dosing.

Ibandronate

Ibandronate (ibandronic acid; Bonviva, Boniva), a nitrogen-containing bisphosphonate available in once-monthly oral and quarterly intravenous formulations for intermittent administration, has been approved for the treatment of osteoporosis in postmenopausal women in the EU, the US and many other countries worldwide. The once-monthly oral formulation has also been approved for the prevention of postmenopausal osteoporosis in the US. Ibandronate is an effective and generally well tolerated bisphosphonate that offers an alternative to other bisphosphonates as a first-line treatment for postmenopausal osteoporosis. It occupies a similar position with respect to the prevention of osteoporosis in postmenopausal women at risk for the disease. The once-monthly oral and quarterly intravenous dosage regimens have the potential to improve treatment adherence and persistence, and hence clinical outcomes, compared with more frequently administered oral bisphosphonates. Intravenous ibandronate may be particularly useful for postmenopausal osteoporotic women who are noncompliant with, or are unable to tolerate or receive, oral bisphosphonates. Thus, intermittent ibandronate extends the range of pharmacological therapies for the treatment and prevention of postmenopausal osteoporosis.

Plasma Concentrations, Pharmacokinetics and Urinary Excretion of Gatifloxacin after Single Intravenous Injection in Buffalo Calves

The pharmacokinetics and urinary excretion of gatifloxacin were investigated after a single intravenous injection of 4 mg/kg body weight in buffalo calves. The therapeutic plasma drug concentration was maintained for up to 12 h. Gatifloxacin rapidly distributed from blood to tissue compartments, which was evident from the high values of the distribution rate constant, alpha1 (11.1 +/- 1.06 h(-1)) and the rate constant of transfer of drug from central to peripheral compartment, k12 (6.29 +/- 0.46 h(-1)). The area under the plasma drug concentration-time curve and apparent volume of distribution were 17.1 +/- 0.63 (microg.h)/ml and 3.56 +/- 0.95 L/kg, respectively. The elimination half-life (t (1/2 beta)), total body clearance (ClB) and the ratio of drug present in tissues and plasma (T/P) were 10.4 +/- 2.47 h, 235.1 +/- 8.47 ml/(kg.h) and 10.1 +/- 2.25, respectively. About 19.7% of the administered drug was excreted in urine within 24 h. A satisfactory intravenous dosage regimen for gatifloxacin in buffalo calves would be 5.3 mg/kg at 24 h intervals.

BI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In Vivo

Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a negative prognostic marker in specific human cancer types . Here, we report the discovery of a potent small-molecule inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concentrations. The compound potently causes a mitotic arrest and induces apoptosis in human cancer cell lines of diverse tissue origin and oncogenome signature. BI 2536 inhibits growth of human tumor xenografts in nude mice and induces regression of large tumors with well-tolerated intravenous dose regimens. In treated tumors, cells arrest in prometaphase, accumulate phosphohistone H3, and contain aberrant mitotic spindles. This mitotic arrest is followed by a surge in apoptosis, detectable by immunohistochemistry and noninvasive optical and magnetic resonance imaging. For addressing the therapeutic potential of Plk1 inhibition, BI 2536 has progressed into clinical studies in patients with locally advanced or metastatic cancers.

Disposition kinetics and urinary excretion of cefpirome after intravenous injection in buffalo calves

We investigated the disposition kinetics and urinary excretion of cefpirome in buffalo calves after a single intravenous administration of 10 mg/kg. Also, an appropriate dosage regimen was calculated. At 1 min after injection, the concentration of cefpirome in the plasma was 57.4 ± 0.72 µg/ml, which declined to 0.22 ± 0.01 µg/ml at 24 h. The cefpirome was rapidly distributed from the blood to the tissue compartment as shown by the high distribution coefficient values (8.67 ± 0.46/h), and by the drug's rate of transfer constant from the central to the peripheral compartment, K12 (4.94 ± 0.31/h). The elimination halflife and the volume of distribution were 2.14 ± 0.02 h and 0.42 ± 0.005 l/kg, respectively. Once the distribution equilibrium was reached between the tissues and plasma, the total body clearance (ClB) and the ratio of the drug present in the peripheral to the central compartment (T/P ratio) were 0.14 ± 0.002 l/kg/h and 1.73 ± 0.06, respectively. Based on the pharmacokinetic parameters we obtained, an appropriate intravenous cefpirome dosage regimen for treating cefpiromesensitive bacteria in buffalo calves would be 8.0 mg/kg repeated at 12 h intervals for 5 days, or until persistence of the bacterial infection occurred.

Disposition kinetics and dosage regimen of levofloxacin on concomitant administration with paracetamol in crossbred calves

The disposition kinetics of levofloxacin was investigated in six male crossbred calves following single intravenous administration, at a dose of 4 mg/kg body weight, into the jugular vein subsequent to a single intramuscular injection of paracetamol (50 mg/kg). At 1 min after the injection of levofloxacin, the concentration of levofloxacin in plasma was 17.2 ± 0.36 µg/ml, which rapidly declined to 6.39 ± 0.16 µg/ml at 10 min. The drug level above the MIC90 in plasma, was detected for up to 10 h. Levofloxacin was rapidly distributed from blood to the tissue compartment as evidenced by the high values of the distribution coefficient, α (17.3 ± 1.65 /h) and the ratio of K12/K21 (1.83 ± 0.12). The values of AUC and Vdarea were 12.7 ± 0.12 µg.h/ml and 0.63 ± 0.01 l/kg. The high ratio of the AUC/MIC (126.9 ± 1.18) obtained in this study indicated the excellent antibacterial activity of levofloxacin in calves. The elimination half-life, MRT and total body clearance were 1.38 ± 0.01 h, 1.88 ± 0.01 h and 0.32 ± 0.003 l/kg/h, respectively. Based on the pharmacokinetic parameters, an appropriate intravenous dosage regimen for levofloxacin would be 5 mg/kg repeated at 24 h intervals when prescribed with paracetamol in calves.

Clinical Utility of a Pharmacostatistical Model for Ibandronate in Postmenopausal Osteoporosis

Ibandronate, a potent, nitrogen-containing bisphosphonate for the treatment of postmenopausal osteoporosis, is the subject of an ongoing clinical development program to explore novel oral and intravenous (i.v.) dosing regimens. As part of this program, an extensive modeling and simulation project was undertaken to develop and validate a pharmacologically realistic mathematical model for ibandronate in osteoporosis, the aim being to identify practical dosing regimens for clinical evaluation. A simplified kinetics of drug action or kinetic-pharmacodynamic (K-PD) model (developed from a 4-compartment pharmacokinetic-pharmacodynamic [PK-PD] model) accurately described the urinary excretion of the C-telopeptide of the alpha-chain of type I collagen (uCTX). The model was extended to consider the effects of supplemental calcium therapy and allow simultaneous fitting of i.v. and oral ibandronate data, and then externally validated. This model was used successfully in the selection of appropriate once-monthly doses for further clinical evaluation and recent clinical studies have confirmed the efficacy of the doses identified. Further development of the model may include investigating the effects of ibandronate on bone mineral density and fracture risk, which would further enhance its clinical utility and predictive value. Although modeling and simulation has been used to explore the efficacy of other bisphosphonates, the extensive program with ibandronate has produced a comprehensively validated model that is the first to be prospectively tested by evaluating novel dosing regimens.

Intravenous ibandronate injections in postmenopausal women with osteoporosis: One‐year results from the dosing intravenous administration study

Although oral bisphosphonates are effective treatments for postmenopausal women with osteoporosis, oral dosing may be unsuitable for some patients. An efficacious intravenously administered bisphosphonate could be beneficial for such patients. Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered using extended dosing intervals, either orally or by rapid intravenous injection. The aim of this study was to identify the optimal intravenous dosing regimen for ibandronate in postmenopausal women with osteoporosis. In a randomized, double-blind, double-dummy, phase III, noninferiority study, we compared 2 regimens of intermittent intravenous injections of ibandronate (2 mg every 2 months and 3 mg every 3 months) with a regimen of 2.5 mg of oral ibandronate daily, the latter of which has proven antifracture efficacy. The study group comprised 1,395 women (ages 55-80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2-L4] bone mineral density [BMD] T score less than -2.5). Participants also received daily calcium (500 mg) and vitamin D (400 IU). The primary end point was change from baseline in lumbar spine BMD at 1 year. Changes in hip BMD and in the level of serum C-telopeptide of type I collagen (CTX) were also measured, as were safety and tolerability. At 1 year, mean lumbar spine BMD increases were as follows: 5.1% among 353 patients receiving 2 mg of ibandronate every 2 months, 4.8% among 365 patients receiving 3 mg of ibandronate every 3 months, and 3.8% among 377 patients receiving 2.5 mg of oral ibandronate daily. Both of the intravenous regimens not only were noninferior, but also were superior (P < 0.001) to the oral regimen. Hip BMD increases (at all sites) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. Robust decreases in the serum CTX level were observed in all arms of the study. Both of the intravenous regimens were well tolerated and did not compromise renal function. As assessed by BMD, intravenous injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) are at least as effective as the regimen of 2.5 mg orally daily, which has proven antifracture efficacy, and are well tolerated.

Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer

Phenoxodiol is a multi-pathway initiator of apoptosis with broad anti-tumor activity and high specificity for tumor cells. Its biochemical effects are particularly suited to reversal of chemo-resistance, and the drug is being developed as a chemo-sensitizer of standard chemotherapeutics in solid cancers. This phase I, single-center trial was conducted to test a continuous intravenous dosing regimen of phenoxodiol in patients with late-stage, solid tumors to determine toxicity, pharmacokinetics, and preliminary efficacy. Phenoxodiol given by intravenous infusion continuously for 7 days on 14-day cycles was dose-escalated on an inter-patient basis at dosages of 0.65,1.3, 3.3, 20.0, and 27.0 mg/kg/day (three to four patients per stratum). Treatment cycles continued until disease progression. Toxicity was based on standard criteria; efficacy was based on changes in tumor burden (WHO); pharmacokinetic analysis was conducted on plasma samples at specified time points during treatment cycles. Nineteen heavily-pre-treated patients with solid tumors received a median of three cycles of treatment (range 1-13); two patients received >or= 12 cycles. No dose-limiting toxicities were encountered, with emesis and fatigue (one patient) and rash (one patient) the only significant toxicities. Stabilized disease was the best efficacy outcome, with one patient showing stable disease at 24 weeks. Pharmacokinetics suggested a linear relationship between dosage and mean steady-state plasma concentrations of phenoxodiol. A 7-day continuous infusion of phenoxodiol given every 2 weeks is well tolerated up to a dose of 27.0 mg/kg/day.