A Study of Carbon-14-Labelled [14C] LOXO-305 (Pirtobrutinib) in Healthy Male Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Carbon-14-Labelled [14C] LOXO-305 (Pirtobrutinib) in Healthy Male Participants (NCT06180954), a non-randomized phase 1 study. The primary outcome is Part 1: Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of LOXO-305 in Plasma Following a Single Oral Dose of [14C]-LOXO-305.

2. Clinical Question

The study’s stated broader aims were to characterize absorption, metabolism, and excretion, identify and characterize metabolites, and assess safety and tolerability. Part 2 was intended to assess absolute bioavailability and radioactivity in plasma, urine, and feces, alongside safety and tolerability. These aims describe distinct questions; the two study parts do not establish a randomized comparison between the oral-only procedure and the oral-plus-intravenous procedure. The record describes healthy male participants rather than a patient population, so its design is directed at pharmacokinetic characterization in that setting. Results for the other stated aims are not reported in the registry record in the information available for this summary.

3. Trial Design

This was a Phase I, open-label, nonrandomized study with a parallel model. It was registered as completed. The record lists a start date of 2020-09-23 and a primary completion date of 2020-11-06. Enrollment was 9. These registry entries describe the registry entry; they do not establish how many participants completed each study procedure or contributed to each analysis.

The study had two parts. In Part 1, participants received a single oral solution dose of 200 mg carbon-14-labelled LOXO-305, with approximately 200 microcurie radioactivity. The primary endpoint was the plasma AUC0-inf of LOXO-305 following this dose. The stated measurement schedule began pre-dose and continued through 360 hours post-dose, with multiple specified collection times. The registry describes study duration as up to approximately 60 days for Part 1.

In Part 2, participants received a single 200 mg oral dose of LOXO-305 as 2×100 mg tablets, followed 2 hours later by a single dose of less than 100 μg radiolabelled LOXO-305, administered by intravenous push over approximately 2 minutes. The stated purposes included assessing absolute bioavailability and evaluating plasma, urinary, and fecal radioactivity and drug-related material. The stated duration was approximately 47 days for Part 2.

Open-label means that masking was not used. Nonrandomized means assignment was not described as random. The registry specifically cautions that the parts are not a like-for-like control comparison. A protocol-level explanation of how participants were allocated between the parts, whether any formal decision rules governed progression, or whether interim analyses were planned is not reported in the registry record. The record also does not report a statistical analysis plan or a sample-size justification. The listed enrollment should therefore be read as the study enrollment, not as evidence of a powered comparative design.

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: All part 1 participants who received \[14C\]-LOXO-305 and had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. Participants were excluded from the analysis if they had an AE of vomiting that occurred at or before 2 times the median time to maximum observed plasma concentration (Tmax).

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 enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Pharmacokinetics (PK): Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of LOXO-305 in Plasma Following a Single Oral Dose of [14C]-LOXO-305, measured over Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360 hours post-dose.

The primary endpoint is the area under the plasma concentration-time curve for LOXO-305 from time zero extrapolated to infinity, abbreviated AUC0-inf. It was specified for Part 1 after a single oral dose of carbon-14-labelled LOXO-305. AUC represents accumulated drug concentration over time: it combines information about the concentration measured at successive sampling times rather than describing concentration at a single moment. Extending the estimate to infinity incorporates an extrapolated terminal portion beyond the observed sampling period.

In general, AUC is used in pharmacokinetic studies to describe systemic exposure. The registry specifies that the reported summary parameter was a geometric mean and that dispersion was to be expressed as a geometric coefficient of variation. These summaries can be useful when pharmacokinetic values are positively skewed or vary multiplicatively: the geometric mean describes a central value on a multiplicative scale, while the geometric coefficient of variation describes relative spread on that scale. This is a general explanation of the statistics, not a claim about the distribution observed in this study.

The scheduled blood sampling extended from pre-dose to 360 hours post-dose, but the endpoint also requires extrapolation beyond observed concentrations. The registry record does not report the Part 1 AUC0-inf estimate, its geometric coefficient of variation, a confidence interval, or participant-level values. It therefore does not allow readers to assess the magnitude or precision of the primary endpoint from the record information. The registry description also gives an analysis population and an exclusion criterion related to vomiting, but does not provide the endpoint result for that population.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record describes the primary endpoint as a geometric mean of AUC0-inf, with a geometric coefficient of variation as the dispersion measure. Those choices matter because concentration-time data can vary substantially among individuals and may have a multiplicative rather than additive pattern of variation. The concepts below are general statistical explanations. The registry does not report enough endpoint estimates to evaluate their realized values in this study.

What does AUC0-inf measure?

AUC0-inf is the area under a concentration-time curve, beginning at time zero and extending to infinity. The observed concentration measurements contribute to the area over the sampling period. The remaining area after the last observation is estimated by extrapolating the terminal decline in concentration. This makes AUC0-inf a summary of overall exposure, but it also means that its estimate depends partly on a model-based extrapolation rather than only on directly observed samples. The registry names the endpoint and states that sampling continued through 360 hours post-dose; it does not report how much of the endpoint was observed versus extrapolated, or the endpoint estimate itself.

Why use a geometric mean?

A geometric mean is calculated on a logarithmic scale and then expressed on the original scale. In general, it is suited to positive measurements whose variation is proportional or multiplicative. For example, values that differ by a similar factor are treated symmetrically on the logarithmic scale. It should not be interpreted as an arithmetic average. The registry specifies the geometric mean for the primary endpoint but does not report participant-level AUC values, the geometric mean, or the details of any log-scale model used to derive it.

What does the geometric coefficient of variation convey?

A coefficient of variation expresses variability relative to a central value. In geometric summaries, the geometric coefficient of variation describes relative spread on a multiplicative scale. It is not a confidence interval and does not by itself indicate how precisely the estimated geometric mean is known. A confidence interval, when reported, gives a range of values compatible with the data and the specified inferential method, subject to its assumptions. No confidence interval for the primary endpoint is reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion means that observed variation is greater than a statistical model’s assumptions allow. If it is ignored in a model that assumes less variability, standard errors can be too small and uncertainty can appear more limited than it is. Appropriate methods depend on the outcome and design. This study’s primary endpoint is a pharmacokinetic exposure measure, and the registry identifies geometric summaries; it does not report an over-dispersion assessment or a model specification. Over-dispersion should not be presumed to have occurred in this trial.

What does nonrandomized, open-label design imply?

In general, random allocation helps make groups comparable on average, while masking can reduce some forms of measurement or behavior-related bias. Neither feature is described for this study: allocation was nonrandomized and masking was none. More importantly, the two parts followed different procedures and addressed different objectives. They are not a like-for-like control comparison, as the registry explicitly notes. The design can describe pharmacokinetic measurements under the stated procedures, but it does not support treating the parts as randomized alternatives. The registry does not report a statistical model intended to adjust for differences between parts.

What can the posted safety counts establish?

Counts of participants with adverse events are descriptive. A serious adverse event count and a count of participants with other adverse events are distinct summaries; neither alone describes event duration, severity gradation, timing, or relationship to treatment. A participant-level count also does not necessarily equal the number of event episodes. The registry lists the number at risk and the number affected for each category, but the details needed to characterize event patterns are not reported. With no randomized comparison, a contrast between the parts would not isolate an effect of the different procedures.

What is missing from the statistical account?

The registry record does not report the primary endpoint estimate, a confidence interval, or a test result. It also does not report a statistical analysis plan, sample-size justification, interim-analysis plan, or full model details. The record lists 51 outcome measures and 0 analyses. Those registry counts do not substitute for numerical endpoint results or a detailed analysis description. No recalculated result is available to compare with a sponsor analysis, and no discrepancy between sponsor and recalculated results is reported. Accordingly, interpretation should not infer a test, precision estimate, or design rationale that is absent from the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 51 outcome measures, but the record does not report a statistical plan describing how multiple outcomes were organized or whether any adjustment for multiplicity was planned. Multiplicity arises when several outcomes, time points, or statistical tests are examined: without an appropriate strategy, the chance of at least one apparently unusual result can increase. This is a general statistical concern, not evidence that a particular multiplicity problem occurred in this study. The record names a primary endpoint, but does not provide a testing hierarchy or analysis plan that would clarify how the other measures relate to it.

The primary analysis population is described as Part 1 participants who received radiolabelled LOXO-305, had at least one quantifiable pharmacokinetic concentration, and had at least one pharmacokinetic parameter computed. Participants with an adverse event of vomiting occurring at or before 2 times the median time to maximum observed are described as excluded. The registry wording ends after “maximum observed,” so the complete definition or context of that criterion is not reported in the registry record. The number of participants excluded under this criterion and the number included in the primary analysis are also not reported.

Missing-data handling is not reported in the registry record. It does not state how missing concentrations, incomplete sampling profiles, or unavailable endpoint calculations were treated. Nor does the record describe sensitivity analyses to examine the influence of missing observations or exclusions. The stated requirement for at least one quantifiable concentration and at least one computed pharmacokinetic parameter defines who could be analyzed, but does not explain how incomplete concentration-time profiles were handled.

These reporting gaps limit the ability to assess whether the analysis population differs meaningfully from enrollment or how robust the primary endpoint would be to missing measurements. They do not establish that data were missing or that the stated criteria caused bias; those details are not reported in the registry record.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

For Part 1, the registry records 0 serious adverse events among 4 participants at risk, 3 participants with other adverse events among 4 at risk, and 0 deaths. For Part 2, it records 0 serious adverse events among 5 participants at risk, 4 participants with other adverse events among 5 at risk, and 0 deaths. These are separate descriptive counts for the two study parts, whose procedures differed.

“Serious adverse event” and “other adverse event” are separate categories in the record. The counts do not indicate whether an event was judged related to study drug, when it occurred, how long it lasted, or how severe a non-serious event was. The registry lists no serious adverse event terms. It does not provide enough detail to infer the number of event episodes from the number of participants affected.

Zero recorded serious adverse events or deaths in these groups should not be read as proof that such events cannot occur, nor as evidence of comparative safety. The study was nonrandomized, and its parts were not like-for-like control groups. The posted counts are a limited description of events recorded for this study, not an estimate of a treatment effect or a basis for conclusions beyond the registry record.

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

The record establishes that a Phase I study was conducted to characterize the absorption, metabolism, and excretion of radiolabelled LOXO-305 and to assess safety and tolerability. It specifies a primary Part 1 pharmacokinetic endpoint, AUC0-inf of LOXO-305 in plasma after a single oral dose, and describes a separate Part 2 procedure intended to assess absolute bioavailability and radioactivity in plasma, urine, and feces. It also gives the planned sampling schedule and study procedures.

The record does not report the numerical primary endpoint result. Readers therefore cannot use this record to judge the observed AUC0-inf value, its variability, or the precision of its estimate. The record also does not provide numerical results for the other stated pharmacokinetic aims. A defined outcome and a completed status do not establish the outcome’s magnitude or direction.

The posted adverse-event counts show that no serious adverse events or deaths were recorded in either part, while other adverse events were recorded among participants in both parts. These counts do not establish causation, comparative safety, or the likelihood of events outside the study setting. Since the study was nonrandomized and the parts had different procedures, they cannot be interpreted as a controlled comparison.

The study involved healthy male participants. Its record does not establish how results would apply to patients or to populations not described. Nor does the entry report a protocol-level rationale for enrollment, a sample-size justification, an interim-analysis plan, or a full statistical analysis plan. Those details should not be inferred.

In general, a small early-phase pharmacokinetic study can be informative about the measurement and characterization of drug exposure under a specified procedure. That general role does not replace the missing numerical results in this registry record. The available information supports a description of design, endpoint, and posted safety counts, but not a conclusion about clinical benefit, lack of benefit, or treatment choice.

13. Why This Trial Matters Statistically

This trial is statistically relevant because it illustrates how pharmacokinetic questions differ from comparative clinical-outcome questions. The primary endpoint summarizes plasma exposure over time, rather than counting a clinical event or comparing health outcomes between randomized groups. AUC0-inf combines observed concentrations with an extrapolated terminal portion, making both the sampling schedule and the approach to estimation relevant to interpretation.

The record also distinguishes two study procedures. Part 1 used an oral radiolabelled solution, while Part 2 used oral tablets followed by an intravenous radiolabelled dose. Those procedures served different pharmacokinetic aims and were not assigned through randomization. Treating the parts as ordinary comparison arms would confuse a descriptive design with a controlled contrast. The registry itself cautions that the arms are not a like-for-like control comparison.

Another statistical lesson is that an endpoint definition does not substitute for a result. The record describes the geometric mean and geometric coefficient of variation for the primary endpoint, yet does not report their numerical values. Without those estimates and uncertainty measures, readers cannot assess the observed exposure or how precisely it was estimated. Clear reporting of the analysis population also matters: the primary population required quantifiable pharmacokinetic data and a computed parameter, while the number meeting those criteria is not reported.

Finally, safety counts require context. The registry provides counts by part, but these are descriptive and do not establish causality or comparative risk. The study’s value as an early-phase characterization effort can be understood from its objectives and design, while conclusions about the numerical pharmacokinetic findings remain constrained by what is not reported in the registry record.

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 most direct limitation for interpretation is that the registry record does not report the primary AUC0-inf estimate or its geometric coefficient of variation. It also does not report a confidence interval or inferential test for that endpoint. Consequently, the magnitude and precision of the main pharmacokinetic result cannot be assessed from the record information.

The stated primary population is narrower than the enrollment description: participants had to receive radiolabelled LOXO-305, have at least one quantifiable concentration, and have at least one pharmacokinetic parameter computed. The record does not state how many participants met those criteria or how many were excluded. It includes an exclusion criterion related to vomiting, but the registry wording is incomplete after “maximum observed,” and further details are not reported.

The design was nonrandomized and open-label, with two parts using different dosing procedures and different pharmacokinetic purposes. The parts are not appropriate like-for-like controls. The record does not report a detailed allocation process, an analysis plan, a sample-size justification, interim analyses, or methods for handling missing data. These omissions restrict assessment of the analysis and its precision; they do not prove that any specific bias or missing-data problem occurred.

Safety reporting is also limited. The registry gives counts of participants at risk and affected, but does not report event timing, severity detail for other adverse events, attribution, or event-level descriptions. It lists no serious adverse event terms. The study population is healthy male participants, which limits direct applicability to other populations. These constraints are specific to the design and information recorded, and should be kept separate from any clinical interpretation not supported by the record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Carbon-14-Labelled [14C] LOXO-305 (Pirtobrutinib) in Healthy Male Participants — NCT06180954.
• Registry record last updated 2025-01-13; status last verified 2024-11.
• Results first posted 2025-01-13.
• 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

The registry describes a completed, Phase I, open-label, nonrandomized study in healthy male participants, with enrollment of 9. Part 1 evaluated pharmacokinetics after a single oral dose of carbon-14-labelled LOXO-305; its primary endpoint was plasma AUC0-inf. Part 2 used oral LOXO-305 tablets followed by an intravenous radiolabelled dose, with objectives that included absolute bioavailability and radioactivity in plasma, urine, and feces.

The record reports safety counts by part: no serious adverse events or deaths are listed, while other adverse events were recorded. The parts were not a randomized, like-for-like comparison. The registry record does not report the numerical primary pharmacokinetic result, its uncertainty, or a full statistical analysis plan. Enrollment should not be assumed to equal the primary analysis population.