Estimation of the impact of noncompliance on pharmacokinetics: an analysis of the influence of dosing regimens

AIMS

To determine whether, for oxybutynin and risperidone, drug exposure is better with less frequent dosing regimens than with regimens that require more frequent dosing.

METHODS

Pharmacokinetic models of oxybutynin (5 mg twice-daily and 10 mg once-daily) and risperidone (2 mg once-daily orally and 25 mg fortnightly intramuscular injection) were developed. Simulations of multiple doses were performed by use of stochastic models of dose-taking compliance and clinic visit attendance.

RESULTS

At therapeutic concentrations and with typical patterns of noncompliance, intramuscular injections of risperidone resulted in a 41% (SD 12%) greater pharmacokinetic coverage than the oral dose, 76% (SD 10%) vs. 35% (SD 7%). No discernable differences were evident between once- and twice-daily formulations of oxybutynin, 29.2% (SD 10%) vs. 29.0% (SD 13%).

CONCLUSIONS

For equivalent doses for each drug, the longer acting preparation of risperidone, but not oxybutynin, is pharmacokinetically more forgiving of noncompliance than the shorter acting counterparts. Further analysis is required to confirm whether these observations are valid clinically.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Patient compliance is better with formulations that require less frequent dosing than with formulations that require more frequent dosing.
• Intramuscular risperidone and long-acting oxybutynin are two examples of medicines reformulated for less frequent dosing.
• However, it is not clear whether better compliance with less frequent dosing regimens translates to improved therapeutic outcome.

WHAT THIS STUDY ADDS

• At equivalent daily doses and typical patterns of compliance, fortnightly intramuscular depot administrations of risperidone provide better pharmacokinetic coverage than once-daily oral dosing.
• Once-daily dosing of oxybutynin is no better at maintaining pharmacokinetic exposure than twice-daily dosing at half strength.
• The use of simulated compliance data as input to pharmacokinetic models is useful to assess the impact of noncompliance on internal drug exposure.

     

Multivariate evaluation of pharmacological responses in early clinical trials – a study of rIL-21 in the treatment of patients with metastatic melanoma

AIMS

Evaluation of the utility of multivariate data analysis in early clinical drug development.

METHODS

A multivariate chemometric approach was developed and applied for evaluating clinical laboratory parameters and biomarkers obtained from two clinical trials investigating recombinant human interleukin-21 (rIL-21) in the treatment of patients with malignant melanoma. The Phase I trial was an open-label, first-human dose escalation safety and tolerability trial with two separate dosing regimens; six cycles of thrice weekly (3/w) vs. three cycles of daily dosing for 5 days followed by 9 days of rest (5+9) in a total of 29 patients. The Phase II trial investigated efficacy and safety of the ‘5+9’ regimen in 24 patients.

RESULTS

From the Phase I trial, separate pharmacological patterns were observed for each regimen, clearly reflecting distinct properties of the two regimens. Relations between individual laboratory parameters were visualized and shown to be responsive to rIL-21 dosing. In particular, novel systematic pharmacological effects on liver function parameters as well as a bell-shaped dose–response relationship of the overall pharmacological effects were depicted. In validation of the method, multivariate pharmacological patterns discovered in the Phase I trial could be reproduced by the dataset from the Phase II trial, but not from univariate exploration of the Phase I trial.

CONCLUSIONS

The new data analytical approach visualized novel correlations between laboratory parameters that points to specific pharmacological properties. This multivariate chemometric data analysis offers a novel robust, comprehensive and intuitive tool to reveal early pharmacological responses and guide selection of dose regimens.     

Once versus individualized multiple daily dosing of aminoglycosides in critically ill patients

Background and objective

The purpose of this study was to evaluate the once daily dosing (ODD) program in critically ill Egyptian patients compared to individualized multiple daily dosing (MDD) in terms of clinical and bacteriological efficacy. In addition, the incidence of nephrotoxicity associated with both regimens in this specific group of patients was assessed.

Methods

Fifty-two patients with suspected or confirmed bacterial infections admitted to the Critical Care Medicine Department, Kasr El-Aini-Cairo University Hospitals comprised the study population. The amikacin group (30 patients) was sub-divided into 14 patients receiving amikacin ODD (1 g i.v.) and 16 patients receiving amikacin in MDD (500 mg i.v./dose). The gentamicin group (22 patients) was sub-divided into 10 patients receiving the drug ODD (240 mg i.v.) and 12 patients receiving gentamicin MDD (80 mg i.v./dose). Amikacin or gentamicin serum levels were determined by the enzyme multiplied immunoassay technique using Emit 2000. MDD regimen was adjusted based on the individual pharmacokinetic parameters using the Sawchuk–Zaske method.

Results

There was no significant difference between the two dosing regimens with regard to clinical and antibacterial efficacy or incidence of nephrotoxicity of both gentamicin and amikacin groups. In the ODD regimen, duration of treatment had no effect on increasing incidence of nephrotoxicity unlike the individualized MDD regimen. No dose adjustments were needed in the once daily dosing regimen since trough concentrations have never been above toxic level.

Conclusions

The study showed that the ODD regimen is preferred in critically ill patients to individualized MDD as shown by comparable efficacy, nephrotoxicity and lesser need for therapeutic drug monitoring and frequent dose adjustments required in the individualized MDD regimen.     

Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist,in adult patients with advanced solid malignancies

Aims

The aim was to characterize the population pharmacokinetics of BYL719 in cancer patients and assess the time course of tumour response in relation to drug exposure and dosing schedule.

Methods

Plasma samples and longitudinal tumour size measurements were collected from 60 patients with advanced solid malignancies who received oral BYL719 once daily (30–450 mg) or twice daily at 120 mg or 200 mg. Non-linear mixed effect modelling was employed to develop the population pharmacokinetic and pharmacodynamic model.

Results

The pharmacokinetics were best described by a one compartment disposition model and transit compartments accounting for the lag time in absorption. The typical population oral clearance and volume of distribution estimates with their between-subject variability (BSV) were 10 l h⁻¹ (BSV 26%) and 108 l (BSV 28%), respectively. The estimated optimal number of transit compartments was 8.1, with a mean transit time to the absorption compartment of 1.28 h (BSV 32%). The between-occasion variability in the rate and extent of absorption was 46% and 26%, respectively. Tumour growth was modelled using a turnover model characterized by a zero order growth rate of 0.581 cm week¹ and a first order death rate of 0.0123 week⁻¹. BYL719 inhibited tumour growth with an IC₅₀ of 100 ng ml⁻¹ (BSV 154%). Model-based predictions showed potential for additional anti-tumour activity of twice daily dosing at total daily dose below 400 mg, but a loss of efficacy if administered less frequently than once daily.

Conclusions

The proposed model provides a valuable approach for planning future clinical studies and for designing optimized dosing regimens with BYL719.     

Hormonal and metabolic effects of morning or evening dosing of the dipeptidyl peptidase IV inhibitor vildagliptin in patients with type 2 diabetes

AIM

This randomized, double-blind, crossover study compared post-prandial hormonal and metabolic effects of vildagliptin, (an oral, potent, selective inhibitor of dipeptidyl peptidase IV [DPP-4]) administered morning or evening in patients with type 2 diabetes.

METHODS

Forty-eight patients were randomized to once daily vildagliptin 100 mg administered before breakfast or before dinner for 28 days then crossed over to the other dosing regimen. Blood was sampled frequently after each dose at baseline (day −1) and on days 28 and 56 to assess pharmacodynamic parameters.

RESULTS

Vildagliptin inhibited DPP-4 activity (>80% for 15.5 h post-dose), and increased active glucagon-like peptide-1 compared with placebo. Both regimens reduced total glucose exposure compared with placebo (area under the 0–24 h effect–time curve [AUE(0,24 h)]: morning −467 mg dl⁻¹ h, P = 0.014; evening −574 mg dl⁻¹ h, P = 0.003) with no difference between regimens (P = 0.430). Reductions in daytime glucose exposure (AUE(0,10.5 h)) were similar between regimens. Reduction in night-time exposure (AUE(10.5,24 h) was greater with evening than morning dosing (−336 vs. −218 mg dl⁻¹ h, P = 0.192). Only evening dosing significantly reduced fasting plasma glucose (−13 mg dl⁻¹, P = 0.032) compared with placebo. Insulin exposure was greater with evening dosing (evening 407 µU ml⁻¹ h; morning 354 µU ml⁻¹ h, P = 0.050).

CONCLUSIONS

Both morning and evening dosing of once daily vildagliptin 100 mg significantly reduced post-prandial glucose in patients with type 2 diabetes; only evening dosing significantly decreased fasting plasma glucose. Although evening dosing with vildagliptin 100 mg tended to decrease night-time glucose exposure more than morning dosing, both regimens were equally effective in reducing 24 h mean glucose exposure (AUE(0,24 h)) in patients with type 2 diabetes.     

Use of oral bisphosphonates by older adults with fractures and impaired renal function

Background:

The manufacturers of oral bisphosphonates (alendronate, risedronate) recommend avoiding use of these drugs in patients with renal impairment. However, many patients who have osteoporosis or who are at risk of fracture are elderly and may have renal impairment. This situation poses a quandary for clinicians in deciding how best to manage osteoporosis in this high-risk population.

Objective:

To synthesize published evidence regarding the use and safety of oral bisphosphonates for patients with impaired renal function.

Methods:

The following databases were searched up to October 2010: PubMed, MEDLINE, Embase, the Cochrane Library, and International Pharmaceutical Abstracts. The following key words and terms were used for the searches: bisphosphonates, alendronate, risedronate, Fosamax, Actonel, “renal failure”, “renal insufficiency”, “chronic kidney disease”, and “end-stage renal disease”. The manufacturers of Fosamax and Actonel were asked to provide information about use of their products in patients with renal impairment, including unpublished pharmacokinetic studies or reports of adverse drug events.

Results:

The search yielded 2 post hoc analyses of safety data, 1 case–control study, 1 case series, 4 retrospective chart analyses, and 2 prospective studies. According to these publications, numerous patients with decreased renal function have received bisphosphonates and have experienced improvement in bone mineral density and/or reduction in risk of fractures, with no increase in adverse effects. Increased renal damage occurred in some individuals with underlying renal disorders, as described in case reports.

Conclusions:

Although the literature is limited, there is evidence that alendronate and risedronate are well tolerated and effective when used by individuals with renal impairment. Further research is required to confirm the benefits and risks of using these medications in patients with renal impairment.     

Achieving Therapeutic Vancomycin Levels in Pediatric Patients

Background:

Vancomycin is widely used to treat infections caused by methicillin-resistant Staphylococcus aureus. Data for dosing and monitoring of this drug in pediatric patients are lacking, and clinicians who are treating children often follow guidelines established for adults.

Objectives:

To examine the total daily doses of vancomycin required to reach therapeutic trough levels (i.e., 10–20 mg/L) in infants, children, and adolescents, and to assess the number of pediatric patients in whom therapeutic trough levels are achieved with current empiric doses (40–60 mg/kg daily).

Methods:

This chart review evaluated patients 1 month to 18 years of age for whom vancomycin was prescribed at a single institution between November 2011 and October 2012. Patients’ demographic characteristics, vancomycin dosing parameters, and subsequent steady-state trough concentrations were analyzed.

Results:

Overall, the proportion of patients who reached therapeutic trough levels with current empiric doses was 39% (74 of 188). The mean total daily dose (± standard deviation) required to achieve therapeutic trough levels was 57.8 ± 11.5 mg/kg for patients 1 to 5 months of age, 68.9 ± 15.4 mg/kg for those 6 to 23 months of age, 65.8 ± 13.0 mg/kg for those 2 to 12 years of age, and 55.7 ± 11.8 mg/kg for those 13 to 18 years of age.

Conclusions:

Common empiric vancomycin dosing regimens (40–60 mg/kg daily) are not high enough to achieve trough levels of 10–20 mg/L in the majority of pediatric patients. Given these data, the authors suggest a starting dose of 60 mg/kg daily for patients 1 to 5 months of age and those 13 to 18 years of age and a starting dose of 70 mg/kg daily for patients 6 months to 12 years of age.     

Extended-interval aminoglycoside therapy for adult patients with febrile neutropenia: a systematic review

Background:

Although the efficacy and toxicity of extended-interval (once-daily) aminoglycoside regimens is well established for immunocompetent patients, there is clinical concern about using this regimen for patients with neutropenia.

Objective:

To summarize and evaluate the literature reporting the clinical efficacy and safety of extended-interval aminoglycosides therapy in adults with febrile neutropenia.

Methods:

A literature search was conducted within PubMed, Embase, and the Cochrane Database of Systematic Reviews to identify studies assessing the use of extended-interval aminoglycosides for treating febrile neutropenia in adults. Articles were categorized by quality of evidence, according to the rating scale of the US Preventive Services Task Force.

Results:

Ten articles were identified: 5 with level I evidence, 1 with level II-2 evidence, and 4 with level III evidence. Review of the 5 studies with level I evidence (all open-label randomized controlled trials), which compared extended-interval dosing with multiple-daily dosing strategies, revealed no evidence to suggest superiority of one regimen over the other in terms of clinical outcomes. In the study with level II-2 evidence (a prospective comparative trial), the response rate was better in the extended-interval group than in the standard-therapy group. Two of the studies with level III evidence (both prospective noncomparative trials) also had acceptable response rates to extended-interval aminoglycoside therapy, with minimal associated nephrotoxicity. In this review, no major differences in rates of nephrotoxicity or ototoxicity were seen between the 2 dosing regimens.

Conclusions:

The use of extended-interval dosing for aminoglycosides, in combination with other recommended antibiotic therapy, is an effective and safe management strategy for immunocompromised patients with febrile neutropenia. In this population, the clinical efficacy and safety of extended-interval dosing does not appear to differ from those of standard dosing. Whether routine or selective pharmacokinetic monitoring in this patient subpopulation leads to improvements in outcomes is yet to be determined.     

Projected inhibition of platelet aggregation with ticagrelor twice daily vs. clopidogrel once daily based on patient adherence data (the TWICE project)

AIM

Twice daily dosing is often perceived as inferior to once daily dosing due to a higher likelihood of missing a dose. However, more important is the extent to which drug action is maintained when doses are delayed or missed. We compared the estimated inhibition of platelet aggregation (eIPA) for ticagrelor twice daily and clopidogrel once daily, based on their pharmacokinetic/pharmacodynamic relationships and patient dosing history data.

METHODS

Drug dosing histories of 5014 patients prescribed cardiovascular medications (primarily antihypertensive medicines) were extracted from an electronically compiled dosing history database. eIPA levels were simulated for 677 twice daily and 677 once daily dosing histories over a 30 day period, based on published onset/offset models for ticagrelor and clopidogrel IPA characteristics.

RESULTS

While many patients treated twice daily missed at least one dose in 30 days, only 25.7% missed two consecutive doses. By comparison, 46.8% of patients treated once daily missed at least one dose. Simulations based on patient adherence over time showed that the average mean eIPA for ticagrelor twice daily remained significantly higher than for clopidogrel once daily (81.1% vs. 55.0%, P < 0.001). Ticagrelor twice daily patients had an eIPA below 10% for 0.20% of the 30 day period compared with 2.05% for clopidogrel once daily (P A= 0.0001).

CONCLUSIONS

The projected level of platelet inhibition remained higher for ticagrelor twice daily than clopidogrel once daily, mainly due to the higher eIPA level achieved with ticagrelor and the relatively low likelihood of missing two consecutive twice daily doses. This modelling and simulation study suggests a therapeutic benefit of ticagrelor over clopidogrel when taking into account the most common dosing omissions.     

Effectiveness of three times daily lansoprazole/amoxicillin dual therapy for Helicobacter pylori infection in Korea

AIM

We compared three times daily dual therapy with standard triple therapy for effectiveness and safety in H. pylori infection.

METHODS

Two hundred and four H. pylori positive patients with peptic ulcer were randomly assigned to one of two regimens: (i) triple therapy with amoxicillin, clarithromycin and lansoprazole twice daily for 2 weeks or (ii) dual therapy with amoxicillin and lansoprazole three times daily for 2 weeks. The success of eradication was evaluated 4 to 5 weeks after completing treatment.

RESULTS

The eradication rate was 82.8% in the triple therapy group and 78.4% in the dual therapy group by per protocol analysis. This difference was not significant (P= 0.573). Adverse events were more frequent in the triple therapy group than in the dual therapy group (P= 0.002).

CONCLUSIONS

Because dual therapy had fewer side effects than triple therapy and a similar eradication rate, dual therapy may provide an acceptable alternative first line therapy for H. pylori eradication in Korea.     

Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers

AIM

To determine the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple oral doses of ticagrelor, a P2Y₁₂ receptor antagonist, in healthy volunteers.

METHODS

This was a randomized, single-blind, placebo-controlled, ascending dose study. Thirty-two subjects received ticagrelor 50–600 mg once daily or 50–300 mg twice daily or placebo for 5 days at three dose levels in two parallel groups. Another group of 16 subjects received a clopidogrel 300 mg loading dose then 75 mg day⁻¹, or placebo for 14 days.

RESULTS

Ticagrelor was absorbed with median t_max 1.5–3 h, exhibiting predictable pharmacokinetics over the 50–600 mg dose range. Mean C_max and AUC for ticagrelor and its main metabolite, AR-C124910XX, increased approximately dose-proportionately (approximately 2.2- to 2.4-fold with a twofold dose increase) over the dose range. Inhibition of platelet aggregation (IPA) with ticagrelor was greater and better sustained at high levels with ticagrelor twice daily vs. once daily regimens. Throughout dosing, more consistent IPA was observed at doses ≥300 mg once daily and ≥100 mg twice daily compared with clopidogrel. Mean IPA with ticagrelor ≥100 mg twice daily was greater and less variable (93–100%, range 65–100%) than with clopidogrel (77%, range 11–100%) at trough concentrations. No safety or tolerability issues were identified.

CONCLUSIONS

Multiple dosing provided predictable pharmacokinetics of ticagrelor and its metabolite over the dose range of 50–600 mg once daily and 50–300 mg twice daily with C_max and AUC(0,t) increasing approximately dose-proportionally. Greater and more consistent IPA with ticagrelor at doses ≥100 mg twice daily and ≥300 mg once daily were observed than with clopidogrel. Ticagrelor at doses up to 600 mg day⁻¹ was well tolerated.     

Impact of noncompliance with alendronate and risedronate on the incidence of nonvertebral osteoporotic fractures in elderly women

AIMS

To evaluate the association between noncompliance with alendronate and risedronate and the risk of nonvertebral osteoporotic fracture in community-dwelling elderly women.

METHODS

A nested case–control study was conducted using the Quebec administrative health databases. To be included in the cohort, women needed to be aged ≥ 68 years and to have initiated treatment with alendronate or risedronate between 1 January 2002 and 31 March 2005. Cases consisted of all women with an incident nonvertebral osteoporotic fracture occurring ≥ 1 year after initiation of therapy. Each case was matched with up to 20 controls using incidence density sampling, according to age (± 1 year) and follow-up duration. A woman was noncompliant if she had a medication possession ratio (MPR) <80% for total follow-up duration. Rate ratios (RR) for fracture were estimated through conditional logistic regression analysis, adjusting for potential confounders.

RESULTS

Among the 30 259 women included in the cohort, 1036 nonvertebral fracture cases were identified and were matched to 20 069 controls. Compared with women with a MPR ≥ 80%, those with a MPR < 80% had a greater risk of nonvertebral fracture [adjusted RR 1.27, 95% confidence interval (CI) 1.12, 1.44]. Considering hip fracture only, the multivariate model yielded similar results, (adjusted RR 1.28, 95% CI 1.02, 1.61).

CONCLUSIONS

Among community-dwelling elderly women, noncompliance with alendronate or risedronate is associated with an increased risk of nonvertebral fracture.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Compliance with alendronate and risedronate is suboptimal.
• Few studies have specifically evaluated the impact of noncompliance with alendronate or risedronate on the incidence of osteoporotic fractures in community-dwelling elderly women.

WHAT THIS STUDY ADDS

• Among community-dwelling elderly women, noncompliance [defined as medication possession ratio (MPR) < 80%] with alendronate or risedronate was associated with a 27% increased risk of nonvertebral fracture [rate ratio (RR) 1.27, 95% confidence interval (CI) 1.12, 1.44].
• This study is the first to assess the impact of noncompliance with bisphosphonates in a subgroup of women aged > 80 years.
• Among women aged > 80 years, MPR < 80% was associated with a 48% greater risk of sustaining a nonvertebral fracture (RR 1.48, 95% CI 1.19, 1.85), compared with women with a MPR ≥ 80%.

     

Ibudilast in healthy volunteers: safety,tolerability and pharmacokinetics with single and multiple doses

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibudilast is an oral drug approved in Asia for asthma.
• Tolerability of 10-mg regimens has been described previously.
• Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers.

WHAT THIS STUDY ADDS

• Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers.
• Higher-dose regimens are relevant for testing in new neurological indications.
• LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast).

AIMS

To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.

METHODS

Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.

RESULTS

Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median T_max was 4–6 h. Mean (SD) steady-state plasma C_max and AUC_0–24 were 60 (25) ng ml⁻¹ and 1004 (303) ng h ml⁻¹, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.

CONCLUSIONS

Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day⁻¹) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.     

Genistein aglycone reverses glucocorticoid-induced osteoporosis and increases bone breaking strength in rats: a comparative study with alendronate

Background and purpose:

Glucocorticoid-induced osteoporosis (GIO) is the leading cause of secondary osteoporosis. Clinical evidence suggests a role for genistein aglycone in the treatment of post-menopausal osteopenia although proof of efficacy in comparison with currently available treatments is still lacking. To clarify this issue, we investigated the effects of genistein on bone compared with alendronate in experimental GIO.

Experimental approach:

A total of 28 female Sprague-Dawley rats were used. GIO was induced by daily injections of methylprednisolone (MP; 30 mg·kg⁻¹ s.c.) for 60 days. Sham GIO animals (Sham-MP) were injected daily with the MP vehicle. At the end of the osteoporosis development period, MP rats were randomized to receive: vehicle (n= 7), genistein aglycone (5 mg·kg⁻¹ s.c.; n= 7) or alendronate (0.03 mg·kg⁻¹ s.c.; n= 7). Treatment lasted 60 days. Sham-MP animals were treated with vehicle for an additional 60 days. At the beginning and at the end of treatments, animals were examined for bone mineral density and bone mineral content. Bone-alkaline phosphatase and carboxy-terminal collagen cross links were determined; femurs were removed and tested for breaking strength and histology.

Key results:

Genistein aglycone showed a greater increase in bone mineral density, bone mineral content and in breaking strength than alendronate and significantly increased bone-alkaline phosphatase (bone formation marker), reduced carboxy-terminal collagen cross links (bone resorption marker), compared with alendronate. Both treatments improved bone histology and the histological score.

Conclusion and implications:

The results strongly suggest that the genistein aglycone might be an alternative therapy for the management of secondary osteoporosis.     

Dose-effect study of domperidone as a galactagogue in preterm mothers with insufficient milk supply, and its transfer into milk

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Domperidone is an effective treatment for some mothers with insufficient milk supply.
• However, dose–effect data are not available, and the safety of domperidone use in both mother and infant has been questioned.

WHAT THIS STUDY ADDS

• Domperidone only increases milk production in about two-thirds of preterm mothers with insufficient milk supply.
• On average, the responders showed increasing levels of milk production with dose escalation from 30 mg to 60 mg daily.
• The amount of domperidone that transferred into breast milk was very low, and the risk to the breastfed infant is minimal.

AIMS

To investigate the possibility of a dose–response relationship for the use of domperidone in treating insufficient milk supply in mothers of preterm infants, and to quantify the exposure of the breastfed infant to domperidone.

METHODS

Six preterm mothers received domperidone (30 mg daily or 60 mg daily) in a double-blind, randomized, crossover trial. Milk production and serum prolactin were measured before and during the trial, and domperidone concentration in milk was measured during drug treatment.

RESULTS

For milk production, two of the mothers were ‘nonresponders’, whereas the other four were ‘responders’ and showed a significant increase in milk production from 8.7 ± 3.1 g h⁻¹ in the run-in phase (mean ± SEM), 23.6 ± 3.9 g h⁻¹ for the 30-mg dose (P = 0.0217) and 29.4 ± 6.6 g h⁻¹ for the 60-mg dose (P = 0.0047). In all participants, serum prolactin was significantly increased for both doses, but the response was not dose dependent. Median (interquartile range) domperidone concentrations in milk over a dose interval at steady-state were 0.28 µg l⁻¹ (0.24–0.43) and 0.49 µg l⁻¹ (0.33–0.72) for the 30-mg and 60-mg doses, respectively. The mean relative infant dose was 0.012% at 30 mg daily and 0.009% at 60 mg daily.

CONCLUSION

In one-third of mothers, domperidone did not increase milk production. In the remainder, milk production increased at both domperidone doses, and there was a trend for a dose–response relationship. The amount of domperidone that transfers into milk was extremely low, and infant exposure via breastfeeding was not considered to be significant.     

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

AIM

Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of ¹⁴C-vismodegib with single and multiple oral doses.

METHODS

Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a ¹⁴C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for ¹⁴C-vismodegib by accelerator mass spectrometry.

RESULTS

Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h⁻¹, 16.4 l and 31.8%, respectively. Parallel concentration–time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h⁻¹ and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing.

CONCLUSION

Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.     

Feasibility of ASsisTed WARfarin Dosing by Clinical Pharmacy Support Assistants (FAST-WARD Study)

Background:

Pharmacy-managed warfarin dosing has been established at Burnaby Hospital, in Burnaby, British Columbia, for over 10 years. With increases in the number and acuity of patients enrolled, it has become challenging to maintain a successful anticoagulation program. The clinical pharmacy support assistant (CPSA) program was initiated to support the provision of clinical pharmacy services. At the time of the study, Burnaby Hospital had 2 CPSAs. It was anticipated that the pharmacy-managed inpatient warfarin dosing service might benefit from support through the CPSA program to maintain a consistent level of delivery.

Objective:

To examine the feasibility of CPSAs supporting the pharmacy-managed inpatient warfarin dosing service at Burnaby Hospital. Feasibility was based on 4 key parameters: knowledge base, accuracy of data collection, dosage recommendations, and time spent on the process.

Methods:

An observational, prospective pilot study was conducted over 3 months. The CPSAs were given appropriate education and training, and their performance was assessed to determine the feasibility of CPSA-assisted warfarin dosing. The CPSAs had to achieve a priori target scores for each of the 4 parameters in order for CPSA-assisted warfarin dosing to be considered feasible.

Results:

After the didactic sections, both CPSAs answered all review questions correctly. The accuracy of data collection (based on 60 patient encounters) was 98.3%. The warfarin regimens recommended by the CPSAs were similar to those recommended by the clinical pharmacists, with doses differing by a mean of 0.46 mg. For 39 (65%) of the 60 patient encounters, the dosing recommendations of CPSAs and clinical pharmacists were identical. The average time spent per patient encounter was 10.5 min.

Conclusion:

With appropriate training and education, it is feasible for CPSAs to support the pharmacy-managed inpatient warfarin dosing program at Burnaby Hospital.     

Evaluation of Defined Daily Dose,percentage of British National Formulary maximum and chlorpromazine equivalents in antipsychotic drug utilization

Objective

The present study was carried out to investigate and compare the three methods for calculating total antipsychotic dose among outpatients with schizophrenia attending primary psychiatric health care centers. The three methods were: Defined Daily Doses (DDDs), chlorpromazine equivalents (CPZeq) and percentages of the British National Formulary (BNF) maximum.

Methodology

Antipsychotic drug dosing data for 250 patients with schizophrenia were investigated by calculating Spearman’s rank correlation coefficients. Factors associated with antipsychotic dose, expressed as DDDs, CPZeq and percentages of the BNF maximum recommended daily dose, were investigated by means of linear regression analysis.

Results

Spearman’s correlation showed that there is a significant relationship between all pairs of the three dosing methods. In all three methods, coherence was strongest when dealing with first generation antipsychotics (FGA). Linear regression analyses showed a high degree of coherence between antipsychotic doses expressed as DDDs, CPZeq and percentages of the BNF maximum recommended daily dose.

Conclusion

All three tested methods are reliable and coherent for calculating antipsychotic dosing.Abbreviations: %BNFmax, percentage of British National Formulary maximum; CPZeq, chlorpromazine equivalents; DDD, Defined Daily Dose (DDD); FGA, first generation antipsychotics; SGA, second generation antipsychotics