Pharmacokinetics of Sotorasib in Healthy Participants and Participants With Moderate or Severe Hepatic Impairment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics of Sotorasib in Healthy Participants and Participants With Moderate or Severe Hepatic Impairment (NCT04887064), a non-randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of Sotorasib.

2. Clinical Question

This is a pharmacokinetic study: its central question concerns drug concentration in plasma, rather than a clinical efficacy outcome. The primary endpoint is maximum observed plasma concentration, assessed at the listed postdose time points through 168 hours. The record also lists secondary pharmacokinetic measures, including unbound concentration and exposure measures, as well as treatment-emergent adverse events.

The design can describe observed concentrations within each group and compare those groups if results are reported. However, because participants were not randomly allocated, differences between groups cannot automatically be attributed to hepatic function alone. The registry record does not report the primary Cmax results, so the central comparison cannot be quantified from the posted results.

3. Trial Design

NCT04887064 is a completed Phase 1 study sponsored by Amgen. The registry record gives the study start as 2021-04-22 and primary completion as 2022-03-09. It lists 20 participants enrolled and describes the study as open-label, non-randomized, and parallel-group. The three groups are labeled Normal Hepatic Function, Moderate Hepatic Impairment, and Severe Hepatic Impairment.

Participants received a single oral dose of sotorasib. The stated purpose was to evaluate its pharmacokinetics in participants with moderate or severe hepatic impairment compared with participants with normal hepatic function. Because allocation was non-randomized, the groups represent categories of hepatic function rather than treatment arms assigned by chance. The registry record does not describe the criteria for assigning participants to these hepatic-function categories, nor does it report additional eligibility details.

The study was unmasked, so it was not described as blinded. The registry record does not report a placebo group or another intervention. It also does not provide the dose amount, a sample-size justification, or details of the statistical analysis plan. The enrolled total is reported, while the safety record lists 7 participants at risk in the normal hepatic-function group, 8 in the moderate impairment group, and 5 in the severe impairment group. Those safety counts should not be assumed to describe every analysis population unless the registry record says so.

The primary endpoint is maximum observed plasma concentration, Cmax, measured over a schedule of postdose time points. Secondary outcomes include treatment-emergent adverse events and unbound pharmacokinetic measures. Although the study is marked completed, the registry record lists 0 analyses. The primary endpoint’s numerical results, uncertainty estimates, and statistical comparison are not reported in the registry record.

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

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: Safety Population: All participants who received sotorasib and had at least 1 postdose safety assessment.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) of Sotorasib, measured over Predose (Hour 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose following administration of sotorasib on Day 1.

The primary endpoint is maximum observed plasma concentration (Cmax) of sotorasib, expressed in ng/mL. It is the highest measured plasma concentration among the scheduled measurements after dosing. The record specifies predose (Hour 0) and postdose measurements at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours following administration on Day 1.

As a pharmacokinetic measure, Cmax describes the observed peak concentration in plasma over the sampling schedule. It is used to characterize drug exposure, alongside other measures that describe exposure over time or drug disposition. A peak measurement is distinct from an area-under-the-curve measure: Cmax concerns the highest observed concentration, while an area measure summarizes concentration over a specified period.

The registry record specifies a geometric mean as the summary measure and a geometric coefficient of variation as the dispersion measure. A geometric mean is a summary suited to positive, potentially right-skewed measurements when analysis is conducted on a logarithmic scale. The geometric coefficient of variation describes relative variability around that geometric summary. These are general statistical interpretations; the registry record does not explain its rationale for choosing them.

No Cmax values, group estimates, confidence intervals, or statistical test results are reported in the registry record. Thus, the endpoint’s definition and measurement schedule are available, but the size and precision of the observed group differences are not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary endpoint measure?

Cmax is the maximum concentration observed in plasma among the scheduled samples. In this study, the registry record specifies sampling from predose through 168 hours after the single dose. A maximum based on scheduled samples is the highest measured value; it is not necessarily the exact concentration at the true biological peak if that peak occurs between sampling times. This is a general feature of concentration sampling, not a reported finding about this study.

The record names the geometric mean and geometric coefficient of variation as the summary and dispersion measures for Cmax. In general, pharmacokinetic measures are positive and may be skewed, so summaries on a logarithmic scale can be useful. The geometric mean summarizes values on a multiplicative scale, while the geometric coefficient of variation describes relative spread. Neither statistic, on its own, indicates whether a difference between groups is statistically precise or clinically important.

What would a group comparison show?

A comparison of pharmacokinetic measurements across hepatic-function groups would describe how the observed concentrations or exposure measures differ in the enrolled participants. In general, a confidence interval expresses uncertainty around an estimate: narrower intervals indicate greater precision, while wider intervals indicate less precision. A p-value, when reported, addresses compatibility between data and a specified null hypothesis under the analysis assumptions; it does not quantify the size or practical importance of a difference.

For this study, group estimates, confidence intervals, and p-values are not reported in the registry record. It is therefore not possible to characterize either the direction or the precision of the primary comparison. The registry record lists 0 analyses. No statistical test or adjustment approach should be inferred from the endpoint description alone.

Why does the design matter?

The study is non-randomized and uses parallel groups. In general, random allocation helps balance measured and unmeasured participant characteristics across assigned groups, on average. Without random allocation, differences between groups can reflect both the grouping characteristic and other differences among participants. This does not make a descriptive pharmacokinetic comparison impossible, but it limits causal interpretation unless the analysis and relevant participant information address potential confounding. The registry record does not report adjustment methods or enough information to evaluate that issue.

The study is also open-label. For a measured concentration, the laboratory result is not the same kind of outcome as a subjective assessment, but open-label status remains part of the design context. The registry record does not describe blinding procedures for sample handling or laboratory measurement.

How should variability be understood?

Pharmacokinetic measurements can vary between participants. A group summary describes a central tendency, while a dispersion measure conveys variability. The geometric coefficient of variation is a relative measure of spread on a multiplicative scale. Greater variability generally makes group estimates less precise for a given amount of information. This is a general statistical point; no numerical variability estimates are reported for this trial in the registry record.

Over-dispersion is a general concern when observed variation exceeds what a statistical model assumes. If present and not handled appropriately, standard errors and confidence intervals may be unreliable. The registry record does not report a model, diagnostics, or an over-dispersion assessment, so none can be attributed to this study.

What do the planning calculations mean?

Planning illustrations based on an observed effect are not observed power and are not the trial’s original sample-size justification. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. In general, such calculations describe how many participants might be needed under those assumptions to detect an effect of the chosen size. They do not show the probability that a treatment works, and they do not replace the study’s observed results.

The registry record does not report a sample-size justification for the study. It also does not report the observed primary effect estimates needed to judge such planning illustrations. Any planning values should therefore be read only as conditional illustrations, not as evidence of precision or as a substitute for the primary analysis.

What remains unspecified?

The registry record does not report the statistical analysis plan, analysis populations, handling of missing samples, or any interim analyses. It does not explain how the geometric summaries were calculated or how comparisons between groups were modeled. These omissions limit assessment of whether the posted endpoint definitions, if followed by a full analysis, would address all sources of uncertainty. The record’s endpoint descriptions should not be treated as a complete account of analytic methods.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 9 outcome measures, including the primary Cmax endpoint and secondary pharmacokinetic and safety outcomes. When multiple outcomes are examined, there is a general possibility of increased false-positive findings if each is tested without accounting for multiplicity. Statistical plans may designate a primary outcome, control error across selected tests, or treat secondary outcomes as descriptive. The registry record does not report a multiplicity strategy, so it is not possible to say whether or how testing across outcomes was controlled.

The record identifies Cmax as the primary endpoint, but it does not report numerical results or analyses for it. It lists 0 analyses overall. No inferential results are available to evaluate, and the absence of reported analyses should not be interpreted as evidence that there was no difference.

Missing-data handling is not reported in the registry record. The record does not state how missing concentration samples, incomplete sampling schedules, or missing safety information were handled, nor does it give the analysis populations for the pharmacokinetic outcomes. Those details matter because the available observations may differ from the observations intended by the design. No assumptions about imputation, exclusion, or sensitivity analyses can be made.

Interim analyses are not reported in the registry record. The sample-size justification and detailed statistical analysis plan are also not reported. These gaps leave uncertainty about prespecified decision rules and analytic procedures; they should not be filled by assuming common practice.

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 record reports safety counts separately for the three hepatic-function groups. For serious adverse events, the counts are 0 of 7 participants at risk in the normal hepatic-function group, 0 of 8 in the moderate impairment group, and 0 of 5 in the severe impairment group. Deaths are recorded as 0 in each group. The record lists 1 participant with other adverse events in the normal hepatic-function group, 2 in the moderate impairment group, and 1 in the severe impairment group.

These are counts, not estimates of comparative risk. The registry record does not list serious adverse event terms, and it does not provide further detail on the types, timing, severity, or duration of the other events. A zero count in these groups means no serious adverse events were recorded in the posted group entries; it does not establish that an event is impossible or that risk is absent.

The safety groups are non-randomized, and their sizes differ. General comparisons of event counts across groups should account for group size and study context, but no adjusted safety comparison is reported. The registry record’s counts are descriptive and do not by themselves establish a difference or similarity in safety between groups.

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

This trial record describes a single-dose pharmacokinetic study of sotorasib across groups defined by hepatic function. It specifies the primary measure, Cmax, and a schedule of plasma sampling through 168 hours. It also identifies additional unbound pharmacokinetic measures and treatment-emergent adverse events as secondary outcomes. These details explain what investigators intended to assess.

The registry record does not report numerical Cmax results, other pharmacokinetic estimates, or inferential analyses. It therefore cannot show how large any exposure difference was, which group had a higher estimate, or how precisely a difference was estimated. Without those results, the record cannot answer the central quantitative comparison. The endpoint definition is not itself evidence of a result.

The study is non-randomized, so any observed group differences would require cautious interpretation. In general, participant characteristics beyond hepatic-function category may differ across groups. A non-randomized comparison can describe the participants studied, but it does not by itself isolate the effect of hepatic impairment from other factors. The registry record does not provide adjustment methods or sufficient details to assess this possibility.

The safety entries report no serious adverse events and no deaths in the listed groups, alongside counts for other adverse events. Those entries are descriptive and should not be treated as proof of no risk or as a definitive comparison of safety. The registry record does not provide event-level descriptions for the serious adverse event fields.

Accordingly, the posted information supports statements about the study’s design, endpoints, sampling schedule, and recorded safety counts. It does not support a conclusion about the magnitude or clinical meaning of a pharmacokinetic difference, nor a claim about whether sotorasib works or does not work. Such conclusions would require reported results and an assessment of their precision and limitations.

13. Why This Trial Matters Statistically

Pharmacokinetic studies ask how a drug is represented in the body over time, and hepatic function is a relevant grouping for a study whose purpose is to compare drug exposure across levels of impairment. This trial’s design centers on a single oral dose and scheduled plasma measurements, with Cmax as the primary endpoint and several additional unbound pharmacokinetic outcomes.

Statistically, the record illustrates the distinction between a well-described measurement plan and an interpretable result. The endpoint and time points are defined, but the registry record does not report group estimates or analyses. Without those, readers cannot assess the size, direction, or precision of the comparison. A completed study status does not supply the missing numerical findings.

The non-randomized parallel-group structure also matters. It allows observations to be organized by hepatic-function group, but group comparisons may reflect participant differences beyond the grouping category. This is a general design limitation, not a claim that a particular confounder occurred. The registry record does not report the information or analysis needed to evaluate potential confounding.

Finally, the study’s safety counts demonstrate why event counts must be interpreted in context. The recorded serious adverse event and death counts are zero in each group, but the groups are small and no comparative safety analysis is reported. The record is useful for understanding what was planned and what safety counts were entered, while leaving the central pharmacokinetic result unanswered.

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 important limitation for interpretation is that the registry record does not report the primary Cmax results or the results for the listed secondary pharmacokinetic outcomes. It lists 0 analyses. Without estimates and uncertainty measures, the magnitude, direction, and precision of group differences cannot be assessed.

The study is non-randomized and parallel-group. As a result, observed differences across hepatic-function categories would not automatically be attributable to hepatic function alone. The registry record does not report participant characteristics, adjustment procedures, or the criteria used to classify impairment, limiting assessment of comparability between groups.

The registry record does not report the dose amount, sample-size justification, statistical analysis plan, analysis populations, handling of missing samples, multiplicity procedures, or interim analyses. It also does not report laboratory procedures or additional details about the timing and completeness of concentration sampling. These omissions restrict evaluation of how the intended measurements were analyzed and how uncertainty was handled.

The safety entries provide counts by group but do not list serious adverse event terms or describe other adverse events in detail. The counts are descriptive, and the record does not report a comparative safety analysis. The group sizes in the safety record are 7, 8, and 5, respectively, which limits how much can be inferred from event counts alone.

These limitations do not change the stated study purpose, but they constrain what can be concluded from the registry record. In particular, the record does not support a numerical pharmacokinetic comparison or a definitive interpretation of safety differences.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics of Sotorasib in Healthy Participants and Participants With Moderate or Severe Hepatic Impairment — NCT04887064.
• Registry record last updated 2024-04-19; status last verified 2023-01.
• Results first posted 2024-04-19.
• 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

NCT04887064 is a completed, open-label, non-randomized Phase 1 study sponsored by Amgen. It enrolled 20 participants and evaluated the pharmacokinetics of a single oral dose of sotorasib in participants with normal hepatic function and moderate or severe hepatic impairment.

The primary endpoint was maximum observed plasma concentration (Cmax), with sampling specified from predose through 168 hours after dosing. Secondary outcomes included treatment-emergent adverse events and additional unbound pharmacokinetic measures. The registry record lists 9 outcome measures and 0 analyses.

Safety entries report 0 serious adverse events and 0 deaths in each group. Other adverse events were recorded for 1 participant with normal hepatic function, 2 with moderate impairment, and 1 with severe impairment. The numerical pharmacokinetic results and statistical comparisons are not reported in the registry record.