Bounded Integer Modeling of Symptom Scales Specific to Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia.

The International Prostate Symptom Score (IPSS), the quality of life (QoL) score, and the benign prostatic hyperplasia impact index (BII) are three different scales commonly used to assess the severity of lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH-LUTS). Based on a phase II clinical trial including 403 patients with moderate to severe BPH-LUTS, the objectives of this study were to (i) develop traditional pharmacometric and bounded integer (BI) models for the IPSS, QoL score, and BII endpoints, respectively; (ii) compare the power and type I error in detecting drug effects of BI modeling with traditional methods through simulation; and (iii) obtain quantitative translation between scores on the three abovementioned scales using a BI modeling framework. All developed models described the data adequately. Pharmacometric modeling using a continuous variable (CV) approach was overall found to be the most robust in terms of type I error and power to detect a drug effect. In most cases, BI modeling showed similar performance to the CV approach, yet severely inflated type I error was generally observed when inter-individual variability (IIV) was incorporated in the BI variance function (g()). BI modeling without IIV in g() showed greater type I error control compared to the ordered categorical approach. Lastly, a multiple-scale BI model was developed and estimated the relationship between scores on the three BPH-LUTS scales with overall low uncertainty. The current study yields greater understanding of the operating characteristics of the novel BI modeling approach and highlights areas potentially requiring further improvement.

Item Response Theory Modeling of the International Prostate Symptom Score in Patients with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia.

Item response theory (IRT) was used to characterize the time course of lower urinary tract symptoms due to benign prostatic hyperplasia (BPH-LUTS) measured by item-level International Prostate Symptom Scores (IPSS). The Fisher information content of IPSS items was determined and the power to detect a drug effect using the IRT approach was examined. Data from 403 patients with moderate-to-severe BPH-LUTS in a placebo-controlled phase II trial studying the effect of degarelix over 6 months were used for modeling. Three pharmacometric models were developed: a model for total IPSS, a unidimensional IRT model, and a bidimensional IRT model, the latter separating voiding and storage items. The population-level time course of BPH-LUTS in all models was described by initial improvement followed by worsening. In the unidimensional IRT model, the combined information content of IPSS voiding items represented 72% of the total information content, indicating that the voiding subscore may be more sensitive to changes in BPH-LUTS compared with the storage subscore. The pharmacometric models showed considerably higher power to detect a drug effect compared with a cross-sectional and while-on-treatment analysis of covariance, respectively. Compared with the sample size required to detect a drug effect at 80% power with the total IPSS model, a reduction of 5.9% and 11.7% was obtained with the unidimensional and bidimensional IPSS IRT model, respectively. Pharmacometric IRT analysis of the IPSS within BPH-LUTS may increase the precision and efficiency of treatment effect assessment, albeit to a more limited extent compared with applications in other therapeutic areas.

Integrated Item Response Theory Modeling of Multiple Patient-Reported Outcomes Assessing Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia.

In clinical trials within lower urinary tract symptoms due to benign prostatic hyperplasia (BPH-LUTS), the International Prostate Symptom Score (IPSS) is commonly the primary efficacy outcome while the Quality of Life (QoL) score and the BPH Impact Index (BII) are common secondary efficacy markers. The current study aimed to characterize BPH-LUTS progression using responses to the IPSS, the QoL, and the BII in an integrated item response theory (IRT) framework and assess the Fisher information of each scale. The power of this approach to detect a drug effect was compared with an IRT approach considering only IPSS responses. A unidimensional and a bidimensional pharmacometric IRT model, based on item-level IPSS responses in a clinical trial with 403 patients, were extended by incorporating patients' QoL and summary BII scores over the 6-month trial period. In the developed unidimensional integrated model, the QoL score was found to be the most informative, representing 17% of the total Fisher information, while the combined information content of the seven IPSS items represented 70.6%. In the bidimensional model, "storage" and both storage and "voiding" disability drove QoL and summary BII responses, respectively. Sample size reduction of 16% to detect a drug effect at 80% power was obtained with the unidimensional integrated IRT model compared with its counterpart IPSS IRT model. This study shows that utilizing the information content across the IPSS, QoL, and BII scales in an integrated IRT framework results in a modest but meaningful increase in power to detect a drug effect.

Dose Finding in the Clinical Development of 60 US Food and Drug Administration-Approved Drugs Compared With Learning vs. Confirming Recommendations.

This review characterizes clinical development that supported the label dose in 60 drug indications recently approved by the US Food and Drug Administration. With Lewis B. Sheiner's Learning vs. Confirming clinical drug development paradigm as a reference point, the clinical development paths, the design of dose-ranging trials, and the dose-exposure-response characterization were examined using US Food and Drug Administration approval packages. It was found that 89% of clinical development programs included several doses in the first-in-patient trial, 43% proceeded directly to confirmatory trials after the first-in-patient trial, and 52% included multiple doses in confirmatory development. A low number of doses and narrow dose ranges were generally included in dose-ranging trials, with only 20% including at least four doses over an at least 10-fold dose range. In a third of approval packages, no dose-response or exposure-response evaluation was identified, and model-based dose-exposure-response characterization was rarely alluded to, as only 2 of 60 approval packages mentioned the use of a model-based approach. The findings suggest that confirmatory development may often be guided more toward learning than confirming, and furthermore that dose exposure response is robustly assessed in only a minority of clinical drug development programs, indicating that there may be room left for optimizing the benefit/risk profile of confirmatory/marketed dose(s). Significant deviation from Learning vs. Confirming may exist in clinical development practice on several levels, and the reasons for why this may be the case are discussed in light of contemporary literature.

Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations.

The carboxylesterase 1 gene (CES1) encodes a hydrolase implicated in the metabolism of commonly used drugs. CES1A2, a hybrid of CES1 and a CES1-like pseudogene, has a promoter that is weak in most individuals. However, some individuals harbor a promoter haplotype of this gene with two overlapping Sp1 sites that confer significantly increased transcription potentially leading to rapid drug metabolism. This CES1A2 haplotype has previously been reported to be common among Asians. Using polymerase chain reaction followed by sequencing, the present study examined variation in the promoter and 5' untranslated region of CES1A2 in 120 Han Chinese and 120 Japanese people enrolled in the 1000 Genomes Project. We identified 11 single nucleotide variations, two of which were novel, in 145 of the individuals who were found to carry CES1A2. Alignment analysis indicated that the CES1A2 haplotype with the overlapping Sp1 sites has been generated by incorporation of a segment of CES1. All minor allele frequencies were equal to or below 0.022 and the frequencies of the minor haplotypes were up to 40-fold lower than previously reported, including that of the haplotype with the overlapping Sp1 sites. This information is novel and suggests that the pharmacogenetic relevance of CES1A2 is limited in Asians.

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers.

This study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time-points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: group 1 (control group, n = 16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n = 5) with four copies of CES1; group 3 (n = 6) harbouring the G143E polymorphism; group 4 (n = 2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n = 4) harbouring the CES1A1c variant; and group 6 (n = 10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 ng/ml x h in the control group versus 310, 282, 294, 344 and 306 ng/ml x h in groups 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared with the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril.

The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects.

AIMS: This study investigated the influence of CES1 variations, including the single nucleotide polymorphism (SNP) rs71647871 (G143E) and variation in copy number, on the pharmacokinetics of a single oral dose of 10 mg methylphenidate. METHODS: CES1 genotype was obtained from 200 healthy Danish Caucasian volunteers. Based on the genotype, 44 (19 males and 25 females) were invited to participate in an open, prospective trial involving six predefined genotypes: three groups with two, three and four CES1 copies, respectively; a group of carriers of the CES1 143E allele; a group of individuals homozygous for CES1A1c (CES1VAR); and a group having three CES1 copies, in which the duplication, CES1A2, had increased transcriptional activity. Plasma concentrations of methylphenidate and its primary metabolites were determined at scheduled time points. RESULTS: Median AUC of d-methylphenidate was significantly larger in the group carrying the 143E allele (53.3 ng ml-1  h-1 , range 38.6-93.9) than in the control group (21.4 ng ml-1  h-1 , range 15.7-34.9) (P < 0.0001). Median AUC of d-methylphenidate was significantly larger in the group with four CES1 copies (34.5 ng ml-1  h-1 , range 21.3-62.8) than in the control group (P = 0.01) and the group with three CES1 copies (23.8 ng ml-1  h-1 , range 15.3-32.0, P = 0.03). There was no difference between the groups with two and three copies of CES1. CONCLUSIONS: The 143E allele resulted in an increased AUC, suggesting a significantly decreased CES1 enzyme activity. Surprisingly, this was also the case in subjects with homozygous duplication of CES1, perhaps reflecting an undiscovered mutation affecting the activity of the enzyme.