Determination of an optimal dosage regimen using a Bayesian decision analysis of efficacy and adverse effect data

One of the aims of Phase II clinical trials is to determine the dosage regimen(s) that will be investigated during a confirmatory Phase III clinical trial. During Phase II, pharmacodynamic data are collected that enables the efficacy and safety of the drug to be assessed. It is proposed in this paper to use Bayesian decision analysis to determine the optimal dosage regimen based on efficacy and toxicity of the drug oxybutynin used in the treatment of urinary urge incontinence. Such an approach results in a general framework allowing modeling, inference and decision making to be carried out. For oxybutynin, the repeated measurement efficacy and toxicity data were modeled using nonlinear hierarchical models and inferences were based on posterior probabilities. The optimal decision in this problem was to determine the dosage regimen that maximized the posterior expected utility given the prior information on the model parameters and the patient response data. The utility function was defined using clinical opinion on the satisfactory levels of efficacy and toxicity and then combined by weighting the relative importance of each pharmacodynamic response. Markov chain Monte Carlo (MCMC) methodology implemented in WinBUGS 1.3 was used to obtain posterior estimates of the model parameters, probabilities and utilities.     

Pharmacokinetics and Metabolism of Transdermal Oxybutynin: In Vitro and in Vivo Performance of a Novel Delivery System

Purpose. The purpose of this work was to characterize in vitro/in vivo delivery and pharmacokinetics of oxybutynin (OXY) and its active metabolite, N-desethyloxybutynin (DEO), by a novel matrix transdermal system (TDS). Methods. Two in vivo, randomized, three-way crossover trials examined single/multiple OXY TDS doses. Abdomen, buttock, and hip application sites were compared and dose proportionality was evaluated. Model independent pharmacokinetics, elimination rate constants, and metabolite/drug ratios were derived from both plasma OXY and DEO concentrations. Results. Single/multiple applications of the OXY TDS to the abdomen yielded mean C _max OXY concentrations of 3.4 ± 1.1/6.6 ± 2.4 ng/mL and median t _max of 36/10 h, with steady state achieved during the second application. Plasma OXY and DEO concentrations decreased gradually after C _max until system removal. Buttock and hip applications resulted in bioequivalent OXY absorption. AUC ratios of DEO/OXY were 1.5 ± 0.4 (single dose) and 1.3 ± 0.3 (multiple dose). Mean in vitro OXY skin absorption (186 g/h) was comparable to the estimated in vivo delivery (163 g/h) over 96 h. Conclusions. Sustained delivery over 4 days and multiple sites allow a convenient, well-tolerated, twice-weekly OXY TDS dosing. A low incidence of anticholinergic side effects is expected during clinical use because of the avoidance of presystemic metabolism and low DEO plasma concentrations. The consistent delivery, absorption, and pharmacokinetics should result in an effective treatment of patients with overactive bladder.     

Effect of food on the bioavailability of oxybutynin from a controlled release tablet

Objective: The effect of food on the bioavailability of oxybutynin was assessed in a randomised cross-over study in 23 healthy volunteers. A single oral 10 mg dose of a controlled release oxybutynin tablet was administered after a high fat breakfast and to fasting subjects. The AUC, C_max, t_max, t_1/2 and MRT of oxybutynin and its active metabolite N-desethyloxybutynin were determined. Results: Breakfast did not change the AUC of oxybutynin but increased the AUC of N-desethyloxybutynin by about 20% . The C_max of oxybutynin and N-desethyl oxybutynin were two-fold higher when the drug was administered after breakfast compared to the fasting state. Conclusion: Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin. Received: 6 October 1995/Accepted in revised form: 26 February 1996     

The pharmacokinetics of oxybutynin in man

Summary We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers.Oxybutynin was rapidly absorbed, maximum plasma concentrations (8 ng·ml^–1) being reached in less than 1 h. The absolute systemic availability averaged 6% and the tablet and solution forms displayed similar relative systemic availability.Plasma concentrations of oxybutynin fell biexponentially, the elimination half-life being about 2 h. There was a large interindividual variation in oxybutynin plasma concentrations. Almost no intact drug could be recovered in the urine. During repeated oral administration steady-state was reached after eight days of treatment.The low absolute systemic availability of oxybutynin, the large interindividual variability in its plasma concentrations, and the apparent absence of intact oxybutynin in the urine suggest that its major pathway of elimination is hepatic metabolism.     

盆底肌训练结合盐酸奥昔布宁在缓解女性膀胱过度活动症中的效果

目的探讨盆底肌训练在缓解女性膀胱过度活动症(OAB)患者症状中的效果。方法选取120例女性OAB患者中配合完成研究者110例,随机分为观察组50例(盆底肌训练加盐酸奥昔布宁治疗)和对照组60例(常规盐酸奥昔布宁治疗),比较2组患者干预前及干预14 d、30 d、90 d、6个月的膀胱过度活动症症状评分(OABSS),比较2组患者干预前及干预14 d、30 d、90 d的盆底肌肌力牛津分级,并比较2组患者干预前及干预90 d、6个月的King生活质量量表评分。结果治疗30 d、90 d后,观察组患者盆底肌力得分分别为(3.23±0.52)、(3.49±0.50)分,高于对照组的(3.03±0.54)、(2.97±0.62)分,差异有统计学意义(P0.05);治疗后6个月随访时,观察组OABSS评分为(1.17±1.87)分,低于对照组的(2.56±2.03)分,差异有统计学意义(P0.05);治疗90 d后,2组King生活质量量表中总体健康感受、行为受限、排尿问题严重性、运动受限、社交受限、症状严重程度得分比较,差异有统计学意义(P0.05)。结论盆底肌训练结合盐酸奥昔布宁治疗能有效缓解女性OAB症状。     

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.

     

Treatment of children with neurogenic bladder dysfunctions using dynamic nero-electrostimulation(DENS) and M-Cholinolytic therapy

【Objective】 To investigate effects of combined usage of dynamic neuro-electric stimulation(DNES) and M-cholynolytic therapy(oxybutynin) upon manifestations of neurogenic bladder dysfunctions(NBD) in children.【Method】 Urodynamics examination included registration of extemporaneous urinary excretion,urofluometry,and retrograde cytometry in horizontal and vertical position by example of urodynamic system(UDS) ACS 180 Plus(MENFIS BioMed.,USA).In accordance to severity of clinician manifestations,three groups of patients have been defined(27-highest one,49-middle and 51 low levels).Dynamic neuro-electrostimulation(DNES) procedures were conducted using theDiaDNES-PKMdevice(Russian Federation).The children were exposed to juxtaspinal stimulation on S1-S3 level-altogether 10 sessions have been performed.Oxybutynin(driptan) was used in dosage of 2.5 mg per diem.【Result】It was established that combined usage of DNES and oxybutynin in the group with highest severity caused the reduction of manifestations by 3.1 times while separately given DNES and basic therapy were followed by 34.1% and 28.0% reduction correspondently.Meanwhile,DNES and oxybutynin reduced severity in patients with pronounced disturbances by 7.5 times.Combined usage of oxybutynin and DNES in severely manifested NBD increased the effective volume of bladder by 2.3 times.Also significant reduction of both intrabladder pressure(by 48.0%) and compliance of the bladder(by 4.8 times) were detected under condition of combined usage of DNES and oxybutynin.All mentioned indices were modified to less extent in case of separate usage of DNES or oxybutynin when compared with the one registered after the combined their usage(P <0.05).【Conclusion】Combined usage of DENS and oxybutinin(driptan) is effective in most severe cases in children suffered from neurogenic overactive bladder.