Integrated population pharmacokinetics of etirinotecan pegol and its four metabolites in cancer patients with solid tumors.

PURPOSE: Etirinotecan pegol (EP), a long-acting topoisomerase-1 inhibitor, is a polyethylene glycol conjugate of irinotecan, with an intended indication for treatment of breast cancer with brain metastases. The objective of this study was to develop a population pharmacokinetic (popPK) model of EP and four of its metabolites (irinotecan, SN38, SN38-glucuronide, and APC) and determine covariates affecting their pharmacokinetics. METHODS: Data from 83 cancer patients enrolled in phase 1 studies were used. The model was developed in two stages: (1) concentration-time data were analyzed with a 3-analyte model for EP, irinotecan, and SN38; and (2) a 5-analyte model developed based on expansion of 3-analyte model to include concentration-time data for SN38 glucuronide and APC with parameter values from 3-analyte model fixed. Covariate relationships with parameters were selected based on Wald's test within the Wald's Approximation Method approach, first for the 3-analyte model then the 5-analyte model. RESULTS: The final integrated popPK model for the five analytes was a two-compartment per analyte model that followed the metabolic cascade of EP to irinotecan, followed by metabolism of irinotecan to the previously known metabolites, but with altered exposures as compared to administration of irinotecan. With the model developed based on total dose of EP, the population estimates of EP clearance and central volume were 0.237 L/h and 5.5 L, respectively. Patient age, body surface area (BSA), and estimated glomerular filtration rate were found to correlate with EP clearance and BSA with EP central volume. Individuals who were homozygous for UGT1A1*28 genotype had modestly reduced elimination capacity of SN38 compared to heterozygous and wild-type genotypes. Simulations evaluating the clinical importance of significant covariates indicated minimal change in areas under the curve and peak concentrations of EP and SN38. CONCLUSIONS: The pharmacokinetics of EP and four metabolites including the active metabolite SN38 were described by an integrated popPK model. Other than BSA, which was already accounted by a BSA-based dosing scheme, no other covariates were deemed to have clinical implications. No EP starting dose adjustment based on patient demographics and other covariates was deemed necessary.

Population Pharmacokinetics of Boosted-Elvitegravir in HIV-Infected Patients.

Elvitegravir (EVG) is an HIV strand transfer integrase inhibitor approved for the treatment of HIV infection as a part of antiretroviral regimens containing cobicistat (COBI) or ritonavir (RTV) as a booster. The population pharmacokinetics of EVG in treatment-naive and -experienced HIV patients was determined, and the effects of demographic, biometric, and formulation covariates on EVG pharmacokinetics (PK) were evaluated. Data from 31 clinical studies (25 in healthy subjects, 6 phase 1b to phase 3 in HIV-1-infected patients) with COBI-boosted EVG studies (as EVG/co or EVG/COBI/FTC/TDF single-tablet regimen) or RTV-boosted EVG studies (EVG/r) were analyzed using NONMEM. The effect of the covariates age, sex, race, health status (healthy volunteers vs HIV patients), weight, body mass index (BMI), body surface area (BSA), creatinine clearance (estimated GFR), and formulation were evaluated. EVG PK, with COBI or RTV, was described by a 2-compartment model, with first-order absorption and elimination and an absorption lag time. A statistically significant, but not clinically relevant, effect of BSA on EVG clearance (CL) was observed. Coadministration of atazanavir or lopinavir with EVG/r had an effect on EVG CL consistent with the known interaction with these agents. No other covariate had a meaningful effect on EVG PK. EVG PK was well described in a population PK model with HIV-infected patients, with low PK variability and no relevant effect of demographic or biometric covariates.

Pharmacokinetic analysis of 14C-ursodiol in newborn infants using accelerator mass spectrometry.

Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of (14) C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of (14) C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants. Five non-cholestatic infants were administered 3 consecutive oral microdoses of (14) C-ursodiol: 8 ng (1.0 nCi), 26 ng (3.3 nCi), and 80 ng (10 nCi) 48 hours apart. Three additional infants with cholestasis were administered a single 80 ng (10.0 nCi) oral dose of (14) C-ursodiol together with a therapeutic dose of 40 mg/kg of non-labeled ursodiol. A pharmacokinetic model describing ursodiol concentrations was developed using nonlinear mixed-effects modeling. The pharmacokinetics of ursodiol in this pilot study were best described by a two-compartment model with first-order elimination. This study demonstrates the feasibility and utility of microdose and microtrace methodology in pediatric research.

Steady-state pharmacokinetics of gabapentin after administration of a novel gastroretentive extended-release formulation in postmenopausal women with vasomotor symptoms.

BACKGROUND AND OBJECTIVE: Approximately 75% of postmenopausal women experience vasomotor symptoms (hot flashes). Currently, hormone replacement therapy is the only approved treatment for hot flashes. However, its use has been associated with an increased risk of invasive breast cancer, coronary heart disease, stroke and venous thromboembolic disease. Gabapentin has also been demonstrated to be efficacious in the treatment of vasomotor symptoms in postmenopausal women when administered three times a day. A gastroretentive extended-release formulation of gabapentin (gabapentin-ER) has recently been demonstrated to be efficacious in the treatment of postmenopausal hot flashes. The objective of this paper is to report the steady-state pharmacokinetics and safety of gabapentin with different dosing regimens of gabapentin-ER in postmenopausal women with hot flashes. METHODS: This was a multicentre, randomized, double-blind, dose-escalating, placebo-controlled, parallel group study in 124 postmenopausal women experiencing ≥7 moderate to severe hot flashes per day. The study consisted of two 5-week treatment periods, with each one preceded by a 1-week titration to the assigned dose. Groups A, B and C received gabapentin-ER 600 mg evening (pm), 600 mg morning (am)/600 mg pm and 1200 mg pm in the first period, and then 600 mg am/1200 mg pm, 600 mg am/1800 mg pm and 1200 mg am/1800 mg pm in the second period, respectively. The tablets were taken after a non-specified meal. Pharmacokinetic sampling was conducted over a 24-hour period at the end of each study period. Plasma samples were analysed by a validated liquid chromatography tandem mass spectrometry method. Non-compartmental pharmacokinetic analysis was performed on the concentration-time data to determine area under the plasma concentration versus time curve from time zero to 24 hours (AUC(24)). Maximum (C(max)), minimum (C(min)) and average (C(avg)) drug concentration and time to reach C(max) (t(max)) were determined by inspection of the data. Tolerability was evaluated by physical examination, clinical laboratory measurements and adverse events monitoring. RESULTS: Gabapentin exposure at steady state, as measured by AUC(24), increased with doses from 600 mg/day to 3000 mg/day, although there was a slight decrease in gabapentin's relative bioavailability with increasing dose compared with the 600 mg dose. The relative bioavailability compared with the 600 mg dose was 86-88% for the 1200 mg/day doses, 75% for the 1800 mg/day dose, 84% for the 2400 mg/day dose, and 73% for the 3000 mg/day dose. C(max) generally increased with increasing dose as did C(min) and C(avg) for the various treatments in a manner that was consistent with the dosing regimen. The values of t(max) were not different between the various doses, with the median t(max) values relative to the most recent dose ranging from 6 to 8 hours for all dose levels. Gabapentin-ER was generally well tolerated at all doses studied. The most common AEs were headache, dizziness and somnolence, with most being mild in intensity. Seven patients withdrew from the study due to AEs. CONCLUSION: The pharmacokinetic profile of gabapentin-ER may allow for once- or twice-daily dosing while maintaining bioavailability and thus efficacy. Gabapentin-ER was well tolerated. CLINICAL TRIAL REGISTRATION: Registered as ClinicalTrials.gov Identifier: NCT00511953.

Drug discovery and development: lessons from an undeveloped drug.

In this article, drug discovery and preclinical development paradigms, as employed in today's pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients. Implementation of systems pharmacology, disease progression and pharmacokinetic/pharmacodynamic models are proposed. These models offer a superior approach in selecting the best drug candidates with the highest chance of success of entry into the market.

Clinical development of metformin extended-release tablets for type 2 diabetes: an overview.

Glumetz (Depomed, Inc., Menlo Park, CA, USA) is a recently approved gastric retentive extended-release formulation of metformin (M-ER) that provides effective, sustained and well-tolerated glycemic control with once daily administration. Pharmacokinetic studies have demonstrated a similar bioavailability of M-ER administered once daily to immediate-release metformin given twice daily. In addition, M-ER has demonstrated a nearly linear dose proportionality with a relative bioavailability of highest dose to lowest dose of 80%, whereas with immediate-release metformin the relative bioavailability of the highest dose to the lowest dose is only 58%. M-ER demonstrated a positive food effect and should be administered with a meal, preferably the evening meal. Because metformin is only eliminated through renal mechanisms, the use of M-ER, as is the case with other formulations, is contraindicated in patients with renal impairment. Administration of M-ER with sulfonylureas (SUs) had no effect on the pharmacokinetics of metformin. In controlled clinical trials M-ER demonstrated efficacy for 24 weeks as a monotherapy or in combination with SU. Additionally, glycemic control was maintained for an extra 24 weeks in an open-label monotherapy extension study of M-ER. M-ER was well tolerated in all studies.

Pharmacokinetics of gabapentin after a single day and at steady state following the administration of gastric-retentive- extended-release and immediate-release tablets: a randomized, open-label, multiple-dose, three-way crossover, exploratory study in healthy subjects.

BACKGROUND: Gabapentin absorption is mediated by a saturable transporter system located in the upper gastrointestinal tract, indicating a short window of absorption. Therefore, conventional sustained formulations would likely result in decreased bioavailability, as the dosage form would pass through the window of absorption before the drug could be completely released. OBJECTIVE: The aim of this study was to compare the pharmacokinetics of an oral, gastric-retentive, gabapentin extended-release (G-ER) formulation with a gabapentin immediate-release (G-IR) formulation after single and multiple daily doses in healthy subjects. METHODS: In this open-label, multiple-dose, 3-way crossover, exploratory study, healthy male and female subjects (aged 18-65 years) were randomized to receive doses of 1800 mg G-ER in accordance with the following regimens: G-ER QD (8 pm), G-ER BID in divided doses (600 mg at 8 am and 1,200 mg at 8 pm), or G-IR TID (600 mg at 8 am, 2 pm, and 8 pm) on day 1 and on days 4 through 8 of each study period. The subjects underwent a 10-day washout between study periods. Gabapentin plasma concentrations were measured in serial plasma samples collected >or=48 hours following dosing on days 1 and 8 using a validated high performance liquid chromatography/tandem mass spectrometry system with a lowest limit of quantitation of 75 ng/mL. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. RESULTS: Of the 24 subjects enrolled in the study, 21 (11 males, 10 females; mean age, 37 years [range, 23- 60 years]; mean height, 172 cm [range, 158-188 cm], mean weight, 77 kg [range, 56-95 kg]; mean body mass index, 26.2 kg/m2 [range, 21.5-29.7 kg/m2]) completed the study. The completing subjects consisted of 8 whites, 7 blacks, 3 Asians, and 3 Hispanics. At steady state, exposure of both G-ER regimens (QD and BID) appeared similar compared with that of G-IR. However, BID dosing resulted in apparently lower C(max) (mean ratio: 81%; CI 90%, 76%-86%) and greater C(min) values (mean ratio: 118%; CI 90%, 107%-130%), while G-ER QD dosing was associated with numerically greater C(max) (mean ratio: 116%; CI 90%, 109%-123%), and lower C(min) values (mean ratio: 52%; CI 90%, 48%-56%) compared with G-IR TID during a 24-hour dosing period. A total of 47 treatment-emergent AEs occurred in 17 patients during the study. The most common AEs were headache (25% G-ER BID divided dose, 10% G-ER QD dosing, and 14% in G-IR TID dosing), dizziness (6%, 0%, and 19%), and muscle cramp (19%, 0%, and 10%). AEs were most prevalent in the G-IR study group. CONCLUSIONS: This exploratory study found that in these healthy subjects, the daily exposure provided by less frequent G-ER dosing was not significantly different from same daily dose with G-IR, administered more frequently. The G-ER BID dosing resulted in less fluctuation, while the G-ER QD dosing produced higher maximum concentrations compared with a G-IR TID regimen.

Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria. * The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults. * No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria. WHAT THIS STUDY ADDS: * This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria. * The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor. * The study proposes dose modification to improve response with the CQ + SDx/PYR combination. AIMS: To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination. METHODS: Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 microl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis. RESULTS: A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (V(C)/F) values were estimated to be 2.84 l h(-1) and 230 l. The typical CL/F for SDx was 0.023 l h(-1), while the factor relating its V(C)/F to normalized body weight was 1.6 l kg(-1). Post hoc parameter estimates for both drugs showed lower maximum concentrations (C(max)) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome. CONCLUSIONS: The study results suggest that full-strength combination to all children would improve the cure rate.

Regadenoson, a selective A2A adenosine receptor agonist, causes dose-dependent increases in coronary blood flow velocity in humans.

BACKGROUND: Regadenoson is a selective A2A adenosine receptor agonist and vasodilator used to increase the heterogeneity of distribution of coronary blood flow during myocardial perfusion imaging. This study characterized the dose dependence of regadenoson-induced coronary hyperemia. METHODS AND RESULTS: An open-label, dose-escalation study of regadenoson (10-500 microg, rapid intravenous bolus) was performed in 34 subjects; in 4 additional subjects, the effect of aminophylline to reverse the response to regadenoson was determined. Intracoronary peak blood flow velocity in either the left anterior descending or left circumflex artery was measured by continuous Doppler signal recording, heart rate, central aortic blood pressure, and adverse effects were recorded. Regadenoson increased peak blood flow velocity by up to 3.4-fold in a dose-dependent manner. The mean duration of the increase in flow velocity of 2.5-fold or greater caused by 400 to 500 microg of regadenoson was 2.3 to 2.4 minutes. Regadenoson (400-500 microg) increased heart rate by up to 21 +/- 6 beats/min and decreased systolic blood pressure (-5 +/- 8 mm Hg to -24 +/- 16 mm Hg) and diastolic blood pressure (-8 +/- 4 mm Hg to -15 +/- 14 mm Hg). Aminophylline (100 mg) attenuated the increase in peak flow velocity but not tachycardia caused by 400 microg of regadenoson. CONCLUSION: The results of this study demonstrate the utility of regadenoson as a coronary vasodilator for myocardial perfusion imaging.

Regadenoson pharmacokinetics and tolerability in subjects with impaired renal function.

The authors have investigated the pharmacokinetics and tolerability of regadenoson, a selective A2A adenosine receptor agonist for use in drug-stressed myocardial perfusion imaging in subjects with varying degrees of renal function. Sixteen subjects with different creatinine clearance values (range: 15-132 mL/min) received a single intravenous bolus dose of 400 microg regadenoson. A population pharmacokinetic model was developed to describe the pharmacokinetics of regadenoson in these subjects. Regadenoson elimination half-life was prolonged with decreasing renal function. However, maximum plasma concentrations, number, or severity of adverse events did not differ significantly between the subjects. Heart rate increased in all subjects after regadenoson injection but returned to normal within 150 minutes. There were no blood pressure pattern differences with respect to renal function. Results from this study do not indicate that dose adjustments are necessary when subjects with decreased renal function are administered the clinically relevant dose of 400 microg regadenoson.

Retrospective analysis of artemisinin pharmacokinetics: application of a semiphysiological autoinduction model.

AIMS: To describe the time-course of the autoinduction of artemisinin by applying a semi-physiological pharmacokinetic model. METHODS: Plasma concentration-time data from six clinical studies involving oral administration of artemisinin to healthy subjects and malaria patients were included in the analysis. NONMEM was used to apply a semi-physiological model incorporating metabolizing enzymes and a pharmacokinetic model including a separate hepatic compartment. RESULTS: The model described the data well. The hepatic extraction ratio increased from 0.74 at pre-induced conditions to 0.98 after autoinduction of metabolism. CONCLUSIONS: Our model successfully described the time-course of autoinduction of metabolism of artemisinin in subjects receiving oral artemisinin.

A population pharmacokinetic/pharmacodynamic analysis of regadenoson, an adenosine A2A-receptor agonist, in healthy male volunteers.

OBJECTIVES: The aims of this study were to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of regadenoson (CVT-3146) in healthy, male volunteers. METHODS: Thirty-six healthy, male volunteers aged 18-50 years were included in this randomised, double-blind, crossover, placebo-controlled study to evaluate single intravenous bolus doses of regadenoson that ranged from 0.1 to 30.0 micro g/kg. Subjects received one dose of regadenoson or placebo on successive days while supine, then the same dose of regadenoson or placebo on successive days while standing. As part of the safety evaluation, vital signs and adverse events were monitored and recorded throughout the course of the study in all subjects. Up to 20 plasma samples were collected for regadenoson concentration determination within the 24 hours after each supine dosage. All urine was collected during the 24-hour time period post-dose and an aliquot was used for the determination of the regadenoson concentration. Heart rate and blood pressure were recorded at many of the same timepoints that the samples for the pharmacokinetic analysis were taken. A non linear mixed-effect modelling approach, using the software NONMEM, was utilised in modelling the plasma and urine concentration-time profiles and temporal changes in heart rate after regadenoson administration in the supine position. The influences of several covariates, including bodyweight, body mass index and age, on pharmacokinetic model parameters were investigated. RESULTS: Adverse events were more prevalent at regadenoson doses above 3 micro g/kg, and the increase in the occurrence of adverse events was dose-related. Most of the adverse events were related to vasodilation and an increase in heart rate and were generally of mild to moderate severity. Based on the severity and frequency of adverse events, the maximum tolerated doses of regadenoson were deemed to be 10 micro g/kg in the standing position and 20 micro g/kg in the supine position. The pharmacokinetics of regadenoson were successfully described by a three-compartment model with linear clearance. Following intravenous bolus dose administration, regadenoson was rapidly distributed throughout the body, followed by relatively slower elimination (terminal elimination half-life of approximately 2 hours). The clearance was estimated to be 37.8 L/h, with renal excretion accounting for approximately 58% of the total elimination. The volume of distribution of the central compartment and the volume of distribution at steady state were estimated to be 11.5L and 78.7L, respectively. Individual pharmacokinetic parameter estimates were fixed in the pharmacodynamic model, where changes in heart rate were related to plasma drug concentrations using a Michaelis-Menten model. The maximum heart rate increase (Emax) and plasma regadenoson concentration causing a 50% increase in the maximum heart rate (EC50) were estimated to be 76 beats per minute and 12.3 ng/mL, respectively. None of the tested covariates was found to be correlated with any of the pharmacokinetic model parameters. CONCLUSIONS: The pharmacokinetics and the effects of regadenoson on heart rate were successfully described using pharmacokinetic/pharmacodynamic modelling. The lack of a correlation between the model estimates and various baseline patient demographics supports unit-based dose administration of regadenoson.

Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin.

PURPOSE: To characterize artemisinin pharmacokinetics (PK) and its antimalarial activity in vivo. METHODS: Artemisinin salivary concentration and parasite count data were obtained from Vietnamese malaria patients receiving two different dosage regimens. PK data were analysed using a previously developed semiphysiological model incorporating autoinduction of eliminating enzymes. A pharmacodynamic (PD) model reflecting different stages of the parasite life-cycle was developed and fitted to the data. The model included visible and invisible compartments as well as sensitive, insensitive, and injured parasite stages. Salivary artemisinin concentrations functioned as the driving force for the observed decrease in the number of parasites. RESULTS: Large interindividual variability was observed in both PK and PD data. The PK model described reasonably well the observed decrease in salivary concentrations after repeated drug administration. The preinduction hepatic extraction ratio of artemisinin was estimated to be 0.87 with a volume of distribution of 27 L. Artemisinin half-life averaged 0.7 h. Incorporation of a saturable hepatic elimination affecting the first-pass extraction as well as a higher intrinsic clearance in female patients resulted in the best fit of the model to the data. The PD model described the decrease in the number of parasites during the course of treatment well. The longest mean transit time of parasites from sensitive, visible to invisible to insensitive visible stages was found to be 34.5 h through one life-cycle. The half-life of injured parasites was 2.7 h. CONCLUSIONS: The proposed semimechanistic PK/PD model successfully described the time course of both salivary artemisinin concentrations after repeated dosing and the number of parasites in patients treated with the drug.

A semiphysiological pharmacokinetic model for artemisinin in healthy subjects incorporating autoinduction of metabolism and saturable first-pass hepatic extraction.

AIMS: Previous studies have shown that the antimalarial drug artemisinin is a potent inducer of its own metabolism in both patients and healthy subjects. The aim of this study was to characterize the time-dependent pharmacokinetics of artemisinin in healthy subjects. METHODS: Twenty-four healthy males were randomized to receive either a daily single dose of 500 mg oral artemisinin for 5 days, or single oral doses of 100/100/250/250/500 mg on each of the first 5 days. Two subjects from each group were administered a new dose of 500 mg on one of the following days after the beginning of the study: 7, 10, 13, 16, 20, or 24. Artemisinin concentrations in saliva samples collected on days 1, 3, 5, and on the final day were determined by HPLC. Data were analysed using a semiphysiological model incorporating (a) autoinduction of a precursor to the metabolizing enzymes, and (b) a two-compartment pharmacokinetic model with a separate hepatic compartment to mimic the processes of autoinduction and high hepatic extraction. RESULTS: Artemisinin was found to induce its own metabolism with a mean induction time of 1.9 h, whereas the enzyme elimination half-life was estimated to 37.9 h. The hepatic extraction ratio of artemisinin was estimated to be 0.93, increasing to about 0.99 after autoinduction of metabolism. The model indicated that autoinduction mainly affected bioavailability, but not systemic clearance. Non-linear increases in AUC with dose were explained by saturable hepatic elimination affecting the first-pass extraction. CONCLUSION: Artemisinin produces a rapid onset of enzyme induction, resulting in a decrease in its own bioavailability over time. The proposed model successfully described the time-course of the onset and normalization of the autoinduction of metabolism in healthy subjects receiving two different dosage regimens of the compound.

Simple solution to a common statistical problem: interpreting multiple tests.

BACKGROUND: The misinterpretation of the results of multiple statistical tests is an error commonly made in scientific literature. When testing several outcome variables simultaneously, many researchers declare a statistically significant result for each test having a P value of <0.05, for example. This approach ignores the fact that, based on a probability result called the Bonferroni inequality, the risk of incorrectly declaring as significant > or =1 test result increases with the number of tests conducted. The implication of this practice is that many scientific results are presented as statistically significant when the underlying data do not adequately support such a claim (sometimes referred to as false-positive results). Although the sequentially rejective Bonferroni test is well known among statisticians, it is not used routinely in scientific literature. OBJECTIVE: The intent of this article was to increase the awareness and understanding of the sequentially rejective Bonferroni test, thereby expanding its use. METHODS: This article describes the statistical problem and demonstrates how the use of the sequentially rejective Bonferroni test ensures that incorrect declarations of statistical significance for > or =1 test result are bounded by 0.05, for example. CONCLUSION: The sequentially rejective Bonferroni test is an easily applied, versatile statistical tool that enables researchers to make simultaneous inferences from their data without risking an unacceptably high overall type I error rate.