A Study of the Effect of Food on Pirtobrutinib (LOXO-305) in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of the Effect of Food on Pirtobrutinib (LOXO-305) in Healthy Participants (NCT06180980), a randomized phase 1 study. The primary outcome is Pharmacokinetics (PK): Area Under the Concentration-time Curve, From Time 0 to 24 Hours Post-dose (AUC0-24) of Pirtobrutinib.

2. Clinical Question

This is a pharmacokinetic question: it concerns the amount of drug measured in the bloodstream over time, rather than whether a treatment changes a disease or improves a health outcome. The registry describes blood sampling from before dosing through 24 hours after dosing on the study days. It also states that the study evaluated safety and tolerability.

The crossover structure means the randomized treatment order was fed then fasted for one sequence and fasted then fed for the other. The record describes a washout period of 7 days between doses. Both conditions used pirtobrutinib; food condition, rather than drug identity or dose, is the contrast of interest. The posted geometric mean AUC0-24 values are 51700.0 h*ng/mL for fasted dosing and 45500.0 h*ng/mL for fed dosing. The posted results do not include a confidence interval or an inferential test for this contrast, so the clinical question can be framed from the reported exposure summaries, but the precision of a fed-versus-fasted estimate cannot be determined from those summaries alone.

3. Trial Design

The registry describes a Phase I, open-label, randomized, two-way crossover study in healthy subjects. The study was completed, with 20 participants enrolled. Its stated purpose was to investigate the effect of food on the pharmacokinetics of a single oral dose of pirtobrutinib, while also evaluating safety and tolerability. The registry lists the study start as 2021-01-04 and primary completion as 2021-03-08.

Participants received 200 mg pirtobrutinib in both treatment conditions. One randomized sequence received the fasted condition first and the fed condition afterward; the other received the fed condition first and the fasted condition afterward. Each dose was administered orally in the morning. The registry describes a 7-day washout period between the doses. In a crossover design, participants contribute observations under both conditions, so comparisons can use within-participant information. The order is randomized to help distribute order-related influences between the sequences; this general design feature does not establish which specific adjustment or model was used for analysis.

The study was open-label, meaning masking was listed as none. Food condition may be apparent to participants and study staff, although the primary endpoint is based on measured plasma concentrations. The posted primary outcome is the geometric mean of AUC0-24, reported separately for fasted and fed dosing, with geometric coefficient of variation as the dispersion measure. The pharmacokinetic population is defined as participants who received one dose, had at least one quantifiable plasma concentration, and had at least one pharmacokinetic parameter computed.

The registry record does not report a sample-size justification, a detailed statistical analysis plan, or the specific model used to account for treatment sequence, period, or participant. It also does not post a treatment-effect estimate with an interval or hypothesis-test result. Those omissions limit how far the displayed summaries can be taken as a formal comparative analysis.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The PK Population was consisted of all participants who had received 1 dose of pirtobrutinib, had at least 1 quantifiable plasma concentration, and for whom at least 1 PK parameter was computed.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: All participants who received at least 1 dose of Pirtobrutinib.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetics (PK): Area Under the Concentration-time Curve, From Time 0 to 24 Hours Post-dose (AUC0-24) of Pirtobrutinib, measured over Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose on Days 1 and 8.

The primary endpoint is the area under the pirtobrutinib concentration-time curve from time zero to 24 hours after a dose, abbreviated AUC0-24. The registry reports this measure in h*ng/mL and summarizes it with a geometric mean. AUC represents accumulated plasma exposure across the measured time interval: it uses information from concentrations at multiple sampling times rather than relying on a single blood concentration. This makes it useful in pharmacokinetic studies that ask how the body handles a drug after administration.

For this study, concentrations were scheduled to be measured before dosing and at multiple post-dose times through 24 hours on Days 1 and 8. The endpoint therefore describes exposure during the first 24 hours after each treatment condition. It is not itself a measure of clinical benefit, disease control, or long-term safety. Nor does AUC0-24 describe exposure beyond the period named by the endpoint.

Geometric means are commonly used for pharmacokinetic measures because concentration and exposure data can be right-skewed. In general, a geometric mean summarizes values on a logarithmic scale and then expresses the result on the original scale. The posted geometric coefficient of variation describes relative variability on a multiplicative scale. It is not a confidence interval and does not by itself show the precision of the estimated difference between fed and fasted conditions.

The registry reports geometric mean AUC0-24 values of 51700.0 h*ng/mL for fasted dosing and 45500.0 h*ng/mL for fed dosing. It does not post a confidence interval for the contrast. As a result, the endpoint summaries describe exposure in each condition, but they do not establish the uncertainty around a comparative estimate.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint summaries are geometric means and geometric coefficients of variation. The registry does not report a treatment-effect estimate, confidence interval, or hypothesis test for the fed-versus-fasted contrast. The following concepts explain how these statistics and the study design are generally interpreted; they do not describe an unreported analysis used in this trial.

What does a geometric mean describe?

In general, the geometric mean is calculated by taking the mean of logarithmically transformed observations and then transforming that mean back to the original measurement scale. It is often used for pharmacokinetic measures because such values can be skewed, with some observations substantially higher than others. A geometric mean is not the same as an arithmetic average, and its value should be understood as a central summary on a multiplicative scale. Here, the registry reports geometric means for AUC0-24 in each food condition, rather than an arithmetic mean.

The reported values are 51700.0 h*ng/mL for fasted dosing and 45500.0 h*ng/mL for fed dosing. Reading those values as separate condition summaries is straightforward. A formal contrast would require an estimate defined on an appropriate scale, such as a ratio of geometric means, together with an uncertainty interval or test. None is posted. No new contrast should be inferred simply by inspecting the two summaries.

What does geometric coefficient of variation mean?

In general, a geometric coefficient of variation describes relative spread on a multiplicative scale and is commonly used with log-transformed pharmacokinetic data. The registry reports 18.7 for the fasted condition and 42.0 for the fed condition. These values summarize variation in the observed exposure data; they are not confidence intervals for the means or for the food-condition effect. A larger dispersion statistic indicates more relative variability in the observations summarized, but it does not alone tell whether a difference between conditions is statistically distinguishable from chance.

Precision of a treatment contrast depends on the design and the variation in paired differences, not only on the separate dispersion summaries. For a crossover comparison, the relationship between each participant’s measurements under the two conditions matters. The registry does not post those paired data or the variance of the paired contrast. Therefore, the reported coefficients of variation cannot be used to reconstruct a confidence interval for the food effect.

Why does the crossover design matter?

In general, a crossover trial assigns participants to receive multiple treatment conditions in sequence. Each participant can serve as their own control, which can reduce the influence of stable differences between participants when estimating a within-person contrast. Randomizing the sequence helps avoid assigning one condition systematically to an earlier or later period. The record describes a randomized two-way crossover with fed-then-fasted and fasted-then-fed orders and a 7-day washout period.

These design characteristics do not reveal the statistical model. A crossover analysis may need to address treatment, period, sequence, and within-participant variation, depending on the protocol and data. The registry record does not report whether or how these elements were modeled, whether assumptions were checked, or whether a carryover assessment was conducted. Those details should not be inferred from the study design alone.

What would an interval add?

In general, a confidence interval communicates the range of effect estimates reasonably compatible with the data and the assumptions of the analysis. Its width gives information about precision: a narrow interval indicates greater precision than a wide one, all else being equal. An interval also helps distinguish a precise estimate from a point estimate that may be uncertain. The registry does not report a confidence interval for the fed-versus-fasted comparison, so the precision of that contrast is not available in the posted results.

A p-value, when reported, addresses how compatible data are with a specified null hypothesis under the analysis assumptions. It does not give the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. No comparative p-value is posted for the primary endpoint. Because neither a contrast interval nor a test result is reported, the condition-level means alone cannot support a conclusion about statistical significance.

What can sample-size planning show?

In general, sample-size planning uses assumptions about the effect of interest, variability, allocation, and a chosen statistical threshold to illustrate how much information a design might need. Such illustrations are not observed power and do not establish the design assumptions used by the investigators. The registry record does not report the trial’s sample-size justification or planning assumptions. The enrollment of 20 participants is a reported study characteristic, not by itself evidence that the study had a particular level of power or precision.

The record also does not post a model-based comparison or a recalculated estimate. The displayed condition summaries can be described as reported, but a statistical comparison requires an explicit estimand and analysis, including appropriate handling of the crossover structure. In the absence of those details, interpretation should remain descriptive and limited to the values and variability measures that are actually reported.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures, but it does not report a multiplicity procedure or a statistical plan for controlling the chance of false-positive findings across multiple outcomes or analyses. The primary endpoint is identified as AUC0-24, but the record does not explain how it was selected relative to other measures or whether any hierarchy of testing was prespecified. No comparative hypothesis test is posted for this primary endpoint. It is therefore not possible to assess the role of multiplicity in any inferential conclusions from the registry record.

Missing-data handling is also not reported in the registry record. The record does not describe how unavailable concentration measurements, incomplete profiles, or other missing observations were handled in the endpoint calculation or comparative analysis. It does not report whether participants with incomplete data were excluded, whether any values were imputed, or what sensitivity analyses were planned or performed. These details matter because missing observations can affect both the composition of the analyzed population and the precision of estimated exposure.

The pharmacokinetic population is defined as participants who received one dose of pirtobrutinib, had at least one quantifiable plasma concentration, and had at least one pharmacokinetic parameter computed. This is an endpoint-related population definition, not evidence that every enrolled participant contributed complete data under both conditions. Although the registry reports 20 participants for each treatment condition and 20 participants enrolled, it does not give a distinct count of participants included in the primary endpoint analysis or detail exclusions.

Interim analyses and stopping rules are not reported in the registry record. Neither is a detailed analysis plan describing treatment of period, sequence, participant effects, or departures from the planned crossover schedule. These omissions limit reproducibility and make it difficult to distinguish a prespecified inferential analysis from a descriptive summary.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for 20 participants at risk under fasted conditions and 20 at risk under fed conditions. The number affected by a serious adverse event is 0 under each condition. Deaths are also reported as 0 in each condition. No serious adverse-event terms are listed among the top serious terms.

For other adverse events, the record reports 2 participants affected among 20 at risk under fasted conditions and 2 among 20 at risk under fed conditions. These are counts, not a complete description of event type, severity, timing, or whether an individual participant experienced events under both conditions. The registry does not list the specific other adverse-event terms in the information available for this summary.

In a crossover study, the same people may contribute to both condition summaries. Thus, condition counts should not automatically be read as observations from two separate groups of participants. The record does not report a paired safety comparison or an inferential analysis. The counts are descriptive and do not establish that the conditions have equivalent safety profiles. A zero count for a recorded category means no such event was reported in the listed group; it does not prove that the risk is absent. The study’s healthy-participant setting and enrollment also limit how broadly these event counts can be applied.

12. What the Result Does, and Does Not, Mean

The results describe pirtobrutinib exposure under two food conditions after a single oral dose in healthy participants. The reported geometric mean AUC0-24 is 51700.0 h*ng/mL when fasted and 45500.0 h*ng/mL when fed. The values indicate that the fasted-condition summary is higher in the posted results. The geometric coefficient of variation is 18.7 for fasted dosing and 42.0 for fed dosing, showing the reported relative spread for each condition.

Those values do not, by themselves, quantify the within-participant food effect. The registry does not report a contrast estimate, confidence interval, or comparative p-value. Without those results, it is not possible to judge the precision of a fed-versus-fasted difference or whether a prespecified statistical criterion was met. Separate condition means and variability measures cannot substitute for a paired comparison in a crossover design.

The findings also do not establish a clinical effect. AUC0-24 is a pharmacokinetic measure of plasma exposure over a defined time interval, not a patient outcome or measure of treatment benefit. The study enrolled healthy participants and tested a single 200 mg oral dose in the morning. The registry record does not support extrapolation to different populations, dosing schedules, meals, or clinical settings.

The safety counts are similarly limited. The registry reports no serious adverse events and no deaths in either condition, and reports 2 participants with other adverse events in each condition. These descriptive counts do not prove equal safety or exclude uncommon or unrecorded events. The record does not provide detailed event terms or a comparative safety analysis.

The most defensible interpretation is therefore narrow: the record reports separate pharmacokinetic summaries for fed and fasted dosing, with the fasted geometric mean higher and the fed geometric coefficient of variation larger. It does not post enough comparative analysis to establish the size or uncertainty of the food-condition contrast. The study does not answer broader clinical questions about treatment effectiveness or safety outside this setting.

13. Why This Trial Matters Statistically

This study is statistically useful as an example of a pharmacokinetic question suited to a randomized crossover design. Food condition is compared while the drug and dose remain the same, and the sequence of conditions is randomized. In general, measuring both conditions in the same participants can make within-participant information valuable because stable person-to-person differences need not dominate the contrast. The design also makes attention to treatment order and period important.

The record illustrates why condition summaries and a treatment comparison are not interchangeable. Geometric means and geometric coefficients of variation describe the distribution in each condition, but they do not show the paired treatment contrast or its uncertainty. In crossover studies, the covariance between a participant’s measurements under the two conditions helps determine the precision of the contrast. The registry does not report that information or a model-based estimate. Readers therefore have a reason to distinguish the descriptive pharmacokinetic results from a formal test of the food effect.

It also highlights the value of transparent reporting. A clear analysis description would identify the population analyzed, the estimand, the model for the crossover structure, and the handling of missing measurements. A treatment-effect estimate with an interval would help readers assess magnitude and precision. These details are not reported in the registry record, so the posted summaries support a restrained interpretation rather than a complete inferential account.

Finally, safety counts in a small healthy-participant pharmacokinetic study answer a different question from the exposure endpoint. Reporting zero serious adverse events and the counts for other adverse events is informative as a descriptive record, but it does not establish comparative safety. Statistical interpretation depends on aligning the claim with the outcome, population, design, and level of uncertainty actually reported.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary limitation is the absence of a posted comparative estimate for fed versus fasted dosing. The registry provides the geometric mean AUC0-24 and geometric coefficient of variation for each condition, but no confidence interval or p-value for the contrast. The summaries therefore do not show the precision of the within-participant comparison.

The record does not report the statistical model, its assumptions, or how treatment sequence, period, and participant effects were handled. It does not describe an assessment of carryover or how the 7-day washout period was evaluated. These are relevant design considerations for a crossover study, but the record does not allow an assessment of how they affected the analysis.

The registry lists 20 participants enrolled and 20 participants in each condition, but it does not give a distinct primary-endpoint analysis count or explain whether every participant contributed a usable paired profile. The pharmacokinetic population definition specifies eligibility based on dose receipt, quantifiable concentration, and computed parameter; details about exclusions and missing data are not reported. No sensitivity analyses are described.

The endpoint is limited to AUC0-24 after a single oral dose and does not describe exposure outside the measured interval. The study involved healthy participants, so the results do not directly characterize pharmacokinetics in patients. The record also does not report meal composition or other details that would support broader statements about all fed conditions. Safety results are sparse: serious events and deaths are listed as zero, while other adverse events are counted without event terms in the record used. The trial’s sample-size justification and detailed analysis plan are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of the Effect of Food on Pirtobrutinib (LOXO-305) in Healthy Participants — NCT06180980.
• Registry record last updated 2025-03-07; status last verified 2025-02.
• Results first posted 2025-03-07.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT06180980 is a completed Phase I, open-label, randomized, two-way crossover study of the effect of food on pirtobrutinib pharmacokinetics in healthy participants. The registry reports 20 participants enrolled. Participants received a single oral 200 mg dose under fed and fasted conditions in randomized order, with a 7-day washout period described between doses.

The primary outcome is geometric mean AUC0-24. The registry reports 51700.0 h*ng/mL for fasted dosing and 45500.0 h*ng/mL for fed dosing, with geometric coefficients of variation of 18.7 and 42.0, respectively. No comparative estimate, confidence interval, or p-value is posted. Safety summaries report 0 serious adverse events and 0 deaths in each condition, with 2 participants affected by other adverse events in each condition.

The record does not report the detailed statistical analysis plan, sample-size justification, missing-data procedures, or analysis of the crossover effects. Interpretation is consequently limited to the reported condition-level summaries and event counts.