Study to Estimate the Effects of Hepatic Impairment on the Pharmacokinetics (PK) of PF-07321332: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Estimate the Effects of Hepatic Impairment on the Pharmacokinetics (PK) of PF-07321332 (NCT05005312), a non-randomized phase 1 study. The primary outcome is Maximum Observed Plasma Concentration (Cmax) of Plasma PF-07321332.

2. Clinical Question

The study was designed to estimate a pharmacokinetic difference associated with hepatic impairment, rather than to test a clinical outcome or compare randomized treatment assignments. Its stated purpose was to inform dosing recommendations, including whether dose or dosing interval might need adjustment in the presence of hepatic impairment. That stated purpose describes the motivation for the study; it does not establish what adjustment is appropriate or whether an adjustment is necessary.

The central statistical question is therefore about the concentration profile represented by Cmax in the two participant groups. The registry specifies a geometric-mean analysis for this endpoint and a sampling schedule extending from predose through 48 hours after dosing. The primary result needed to answer the question would include the group summaries and a clearly defined contrast with its uncertainty. Those numerical results are not reported in the registry record. Without them, the direction, magnitude, and precision of any observed difference cannot be described.

Because assignment was not randomized, the comparison is observational with respect to hepatic-function group. The record identifies the groups as healthy participants with normal hepatic function and participants with moderate hepatic impairment, but the information available does not establish that they were similar in other characteristics. Thus, the study’s question is specifically about the observed pharmacokinetic comparison between these groups, not proof that hepatic impairment alone caused any difference.

3. Trial Design

This was a Phase 1, non-randomized, open-label, parallel study. It evaluated PF-07321332 boosted with ritonavir in adults with moderate hepatic impairment and healthy participants with normal hepatic function. The study record reports an enrollment of 17 and lists two cohorts: Cohort 1, described as healthy volunteers, and Cohort 2, described as participants with hepatic impairment. The safety summaries list 8 participants at risk in each hepatic-function group. The record does not explain the relationship between the enrollment figure and the group counts in those summaries.

Non-randomized means participants were not assigned at random to the hepatic-function groups. Open-label means masking was not used. A parallel design means the groups are considered alongside one another rather than described as a crossover in which participants receive both conditions. These design labels describe how the study was structured; they do not establish that the groups were comparable on characteristics other than hepatic function. The record does not report a randomized control comparison.

The listed primary endpoint is maximum observed plasma concentration of PF-07321332, measured in micrograms per milliliter (ug/mL). Sampling was scheduled at predose and at several post-dose times on Day 1, with further measurements on Day 2 and Day 3, ending at 48 hours. The outcome description says Cmax was directly observed from the concentration data. The primary analysis population was treated participants with at least one primary pharmacokinetic parameter measured.

The study status is completed. The reported start date is 2021-08-31, and the primary completion date is 2021-12-07. The record identifies Pfizer as the sponsor. It also lists secondary safety outcomes concerning treatment-emergent adverse events, electrocardiograms, vital signs, and laboratory assessments. Specific doses, eligibility criteria, participant characteristics, and details of the statistical analysis plan are not reported in the registry record.

The study’s stated objective was to estimate the effect of hepatic impairment on the plasma pharmacokinetics of PF-07321332 with ritonavir. The record says findings would be used in developing dosing recommendations. That objective is distinct from demonstrating a treatment effect on a health outcome: the primary endpoint is a drug concentration measure, and the design is not a randomized clinical-outcome trial.

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.

Before assignment: Seventeen participants were assigned to treatment. One participant in the moderate hepatic impairment group was excluded from the safety and pharmacokinetic (PK) analysis set as this participant was randomized but was discontinued on Day 1 prior to dosing with study treatment PF-07321332. All 16 treated participants included 8 participants without hepatic impairment (Cohort 1) and 8 participants with moderate hepatic impairment (Cohort 2) completed the study.,

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The PK parameter analysis population was defined as all participants assigned to investigational product and treated who had at least 1 of the PK parameters of primary interest measured.

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 who received at least one dose of study intervention.

6. Primary Endpoint

The registry lists the primary outcome as Maximum Observed Plasma Concentration (Cmax) of Plasma PF-07321332, measured over Day 1 at 0 (pre-dose for PF-07321332), 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours, Day 2 at 24 and 36 hours, and Day 3 at 48 hours.

The primary endpoint is the maximum observed plasma concentration, or Cmax, of PF-07321332. It represents the highest measured concentration during the scheduled sampling period. The endpoint is reported in micrograms per milliliter (ug/mL), with the registry specifying a geometric mean and geometric coefficient of variation as its summary statistics.

As a general pharmacokinetic concept, Cmax is used to characterize the peak concentration reached after administration. It is one feature of a concentration-time profile; it does not by itself describe the full profile or the total exposure over time. Other pharmacokinetic parameters may address different aspects of the profile, but the registry’s named primary endpoint is Cmax. The record lists 7 outcome measures overall, but the specific numerical Cmax summaries are not reported in the registry record.

The endpoint was measured by direct observation of concentration data at scheduled times. The registry says values below the lower limit of quantification were set to zero. It also says zero values were excluded from the geometric-mean and geometric-coefficient-of-variation calculations. These handling rules matter because a geometric summary is calculated on a logarithmic scale, where zero cannot be included as an ordinary logged value. The record does not report how many measurements were below the quantification limit.

Cmax is relevant to the study’s stated question because it allows the peak measured concentration to be compared between participants with moderate hepatic impairment and healthy participants with normal hepatic function. To interpret that comparison, readers would need the group estimates and a measure of uncertainty, such as a confidence interval. Those numerical results are not reported in the registry record, so neither the size nor the precision of the comparison can be described from the available information.

The endpoint is a pharmacokinetic measure, not a direct measure of symptoms, disease progression, or clinical benefit. A difference in Cmax, if observed, would describe a difference in this concentration summary; its clinical implications would require additional evidence and context not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the geometric mean summarize?

The registry reports Cmax using a geometric mean and a geometric coefficient of variation. In general, the geometric mean summarizes positive measurements after taking logarithms, averaging on that scale, and transforming back. This approach can be useful for concentration measurements that vary multiplicatively or have a right-skewed distribution. It differs from an arithmetic mean, which summarizes values through ordinary addition and averaging. The registry specifically states that its geometric-mean analysis was on the log scale.

The geometric mean should be interpreted as a central summary of the measured concentrations, not as the concentration of every participant or the value for a typical individual in every relevant sense. Participant-level values can vary around the summary. To understand that variation and the uncertainty in the group comparison, readers would need the reported dispersion and an interval estimate. The numerical group summaries and confidence intervals are not reported in the registry record, so those features cannot be assessed.

What does the geometric coefficient of variation convey?

The geometric coefficient of variation describes relative variability around a geometric summary and is expressed as a percentage in this record. As a general concept, a variability measure helps distinguish a tightly clustered set of measurements from a more dispersed set. Relative variability is often useful for pharmacokinetic measurements because the scale of variation may increase with the level of the measurement. The coefficient is not an estimate of the difference between the hepatic-function groups, and it is not a confidence interval for that difference.

Over-dispersion is a general concern when observations vary more than an analysis model expects. If variability is underestimated, uncertainty intervals may be too narrow and statistical tests may be poorly calibrated. That general issue cannot be evaluated from the registry information: the numerical estimates, individual-level distribution, and detailed model specification are not reported in the registry record. The record’s use of geometric summaries alone does not show whether a particular model accounted for all relevant variation.

How does the endpoint relate to the sampling schedule?

Cmax was directly observed from concentration data collected at scheduled times. The schedule included predose and post-dose measurements on Day 1, followed by measurements on Day 2 and Day 3, with the final listed measurement at 48 hours. As a general principle, a directly observed maximum is the largest measured value among the observations used for the endpoint. It is not necessarily identical to the true peak between measurement times, because concentrations between scheduled samples are not directly observed. The registry describes direct observation but does not report whether any interpolation or model-based estimation supplemented that procedure.

The timing of samples therefore defines the observations from which the maximum is selected. The schedule covers multiple times, giving the endpoint an opportunity to capture a peak during the stated period. The record does not provide concentration-time plots or participant-level measurements in the information available for this analysis. It is not possible to determine from the schedule alone when the peak occurred, how often it occurred at a particular sampling time, or how concentrations changed between measurements.

How are values below quantification handled?

The registry states that concentration values below the lower limit of quantification were set to zero. It further states that zero values were not included in calculations of the geometric mean or geometric coefficient of variation. This is important because the logarithm of zero is undefined, so zero cannot be treated as a regular positive measurement in the stated log-scale calculation. The description identifies the handling rule, but it does not give the count of below-limit values or explain whether additional sensitivity analyses were conducted.

In general, handling below-limit measurements can affect summaries, particularly when such measurements occur frequently or differ across groups. The choice of method should be understood in relation to the study’s concentration data and its intended estimand. The available record does not report enough detail to evaluate how the stated rule affected the estimates. No alternative handling analysis is reported in the registry record.

What can be concluded from a non-randomized comparison?

The two groups were defined by hepatic function, and allocation was non-randomized. As a general statistical principle, randomization can help balance both measured and unmeasured characteristics across assigned groups. It was not used to create the hepatic-function groups in this study. Therefore, a between-group difference in the observed pharmacokinetic summaries cannot automatically be attributed solely to hepatic impairment. Other differences between the groups may also be relevant, and the registry information does not describe a covariate-adjusted analysis.

The parallel structure means the groups are assessed alongside one another. The comparison is not a within-participant crossover contrast in the registry description. Open-label status indicates that masking was not used, but masking is less directly relevant to an objectively measured concentration than it may be to a subjective outcome. That general observation does not establish that measurement, conduct, or analysis was free of bias; the registry does not report enough detail to assess those processes.

What uncertainty information is needed?

A confidence interval is a general statistical summary of uncertainty around an estimate. It gives a range of values compatible with the data and the method’s assumptions; it is not a guarantee that the true value lies in that range. For a group comparison, an interval around the contrast would help readers assess both the direction and precision of the estimated difference. A p-value, if reported, would address a different question about compatibility with a specified null model and would not measure effect size or clinical importance.

The registry information available for this analysis does not include the numerical Cmax estimates, a contrast, confidence intervals, or a p-value. It also does not report the detailed model, a prespecified hypothesis test for the primary endpoint, or the treatment of potential covariates. The statistical analysis plan is not reported in the registry record. Accordingly, no specific inferential result can be reconstructed or interpreted from the endpoint description alone.

The record states that the study had 7 outcome measures and 3 analyses, but it does not give enough detail to map every analysis to an outcome or to infer which analysis produced a particular result. The primary endpoint definition and its calculation rules are available; the numerical findings and broader model specification are not. Statistical interpretation should distinguish those documented features from methods that are not reported.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 7 outcome measures and 3 analyses. It names Cmax as the primary outcome and lists secondary safety outcomes covering treatment-emergent adverse events, abnormal electrocardiograms, abnormal vital signs, and abnormal laboratory assessments. These entries show that the study considered more than one outcome, but the information available does not describe how the analyses were mapped to each outcome or how the registry’s outcome count relates to the listed categories.

Multiplicity arises when several hypotheses or outcomes are assessed. As a general statistical principle, testing many hypotheses can increase the chance of finding an apparently unusual result by chance if no adjustment or hierarchy is specified. A prespecified primary endpoint can help clarify which result is central, but it does not by itself explain how secondary outcomes were handled. The registry record does not report a multiplicity adjustment, a testing hierarchy, or the statistical plan for the secondary outcomes. It would therefore be inappropriate to assume that a particular adjustment was used or that all reported analyses were intended as confirmatory.

The registry defines the pharmacokinetic analysis population as treated participants with at least one primary pharmacokinetic parameter measured. This is a population definition, not a complete account of missing-data handling. The number of participants with missing samples, the reasons for missingness, and any imputation or sensitivity analysis are not reported in the registry record. The treatment of below-limit values is described separately: those values were set to zero, and zero values were excluded from the geometric-mean and geometric-coefficient-of-variation calculations.

Interim analyses, stopping rules, and a detailed statistical analysis plan are not reported in the registry record. Their absence from the information available does not establish that such procedures were or were not used; it means the record does not support a claim about them. Without those details and the numerical results, the extent to which multiplicity, missing observations, and analysis-population choices affect interpretation cannot be assessed.

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

The safety summaries list serious adverse events and other adverse events separately for the two hepatic-function groups. In the normal hepatic function group, 8 participants were at risk; 0 were reported with a serious adverse event, and 3 were reported with other adverse events. In the moderate hepatic impairment group, 8 participants were at risk; 0 were reported with a serious adverse event, and 4 were reported with other adverse events. Deaths are listed as 0 in both groups. No serious adverse event terms are listed.

These are participant counts, not estimates of comparative risk. The record does not report a statistical test or uncertainty interval for the safety comparison. With a small study, descriptive counts can be useful for reporting what was observed but provide limited information about uncommon events or differences that might arise in a larger population. That is a general limitation of interpreting safety counts, not evidence that an unreported event occurred.

The summary does not establish that the groups had identical safety profiles, nor does it establish a causal difference between them. Participants were not randomized to hepatic-function status, and the registry’s safety information does not describe event timing, duration, severity beyond the serious/non-serious grouping, or attribution to study drugs. Those details are not reported in the registry record. The counts should therefore be read as descriptive observations within this study, without broader conclusions.

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

The record documents a completed Phase 1 study intended to estimate the effect of moderate hepatic impairment on the pharmacokinetics of PF-07321332 boosted with ritonavir. It identifies Cmax as the primary endpoint, specifies the sampling times, and describes the use of geometric summaries on the log scale. It also reports descriptive safety counts for participants with normal hepatic function and participants with moderate hepatic impairment. These features establish the study’s objective and some of its measurement and reporting procedures.

The numerical primary pharmacokinetic results are not reported in the registry record. Without group estimates and an uncertainty measure, the posted information does not show the direction, size, or precision of a Cmax difference. No conclusion about whether concentrations were higher or lower in either group can be drawn from the endpoint definition or study objective alone. A study designed to estimate a difference is not itself evidence of the direction or magnitude of that difference.

Even if a difference were reported, Cmax would describe the highest observed concentration during the sampling period, not every dimension of drug exposure or a clinical outcome. The study’s stated purpose was to inform dosing recommendations, but the record does not provide a dose recommendation or numerical findings from which one could be assessed. The information available also does not report the detailed analyses needed to evaluate uncertainty, missing data, or potential adjustment for differences between groups.

The safety counts show that the registry lists 0 serious adverse events in each group and deaths of 0 in each group, alongside other adverse events in 3 participants with normal hepatic function and 4 with moderate hepatic impairment. These figures are descriptive and do not establish that the treatment is safe or unsafe, or that the groups differ. The record does not include enough statistical detail to make a comparative safety claim.

In short, the registry describes the question, design, endpoint, and selected safety counts, but the numerical primary result and its precision are not reported in the registry record. The available information supports a description of what the study set out to assess and how Cmax was defined. It does not support claims about the size or clinical meaning of a pharmacokinetic effect.

13. Why This Trial Matters Statistically

This study illustrates a common distinction in clinical research between a study’s aim and its reported result. The stated aim was to estimate the effect of hepatic impairment on PF-07321332 pharmacokinetics with ritonavir. The primary endpoint is clearly defined as maximum observed plasma concentration, with an explicit sampling schedule and summary method. Yet the numerical Cmax results are not reported in the registry record. A well-defined endpoint helps readers understand what was measured, but it cannot substitute for an estimate and its uncertainty.

The design also makes the comparison’s interpretation important. A non-randomized study can describe differences between groups, but the hepatic-function groups are not randomized treatment arms. Statistical reading must therefore distinguish an observed group contrast from a causal effect that would require stronger assumptions or additional evidence. The registry information available does not report an adjusted model or enough participant characteristics to evaluate comparability.

Pharmacokinetic studies often use summaries such as geometric means because concentration measurements may be better described on a logarithmic scale. The record’s explicit description of log-scale analysis, geometric variability, and handling of below-quantification values makes several methodological choices visible. At the same time, missing numerical estimates and details about below-limit observations prevent readers from assessing the practical influence of those choices.

Finally, the study shows why safety counts and pharmacokinetic outcomes should be interpreted separately. The record reports participant counts for serious and other adverse events, while the primary question concerns drug concentration. Descriptive safety counts do not answer the pharmacokinetic question, and a concentration endpoint does not by itself establish a clinical safety or benefit outcome. Keeping these outcomes distinct helps avoid overstating what a small, non-randomized Phase 1 study can establish.

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 principal limitation for interpreting the primary endpoint is that the numerical Cmax results are not reported in the registry record. Group summaries, a contrast estimate, confidence intervals, and p-values are not available in the information used for this analysis. As a result, the magnitude, direction, and precision of the primary comparison cannot be evaluated.

The non-randomized design limits causal interpretation. The study compares participants by hepatic-function group, but the available record does not establish comparability on other characteristics or describe adjustment for potential differences. Open-label status is reported, but details about conduct, measurement procedures beyond the endpoint definition, and analysis safeguards are not reported in the registry record.

The record gives an enrollment of 17, while safety summaries list 8 participants at risk in each group. It does not explain how these figures relate, nor does it report the number included in the primary pharmacokinetic analysis. The defined analysis population requires treatment and at least one primary pharmacokinetic parameter measured, but the number meeting that definition is not reported in the registry record.

Below-limit concentrations were set to zero and excluded from geometric summaries, but the number and distribution of such observations are not reported. Missing samples, reasons for missingness, and sensitivity analyses are also not reported in the registry record. The detailed model, multiplicity procedures, interim analyses, and statistical plan are not reported either.

The safety summaries are descriptive and do not include comparative inference or detailed event characteristics. The study’s stated purpose was to inform dosing recommendations, but the numerical results and any resulting recommendation are not reported in the registry record. These limitations mean the registry information supports a description of study design and endpoint methods, but not a quantitative conclusion about pharmacokinetic differences or their implications.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study to Estimate the Effects of Hepatic Impairment on the Pharmacokinetics (PK) of PF-07321332 — NCT05005312.
• Registry record last updated 2023-09-06; status last verified 2022-10.
• Results first posted 2023-09-06.
• 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

NCT05005312 is a completed Phase 1, non-randomized, open-label, parallel study sponsored by Pfizer. It enrolled 17 participants and examined PF-07321332 boosted with ritonavir in healthy participants with normal hepatic function and participants with moderate hepatic impairment. The reported start date is 2021-08-31, and the primary completion date is 2021-12-07.

The primary endpoint was maximum observed plasma concentration of PF-07321332, summarized using a geometric mean and geometric coefficient of variation. Concentrations below the lower limit of quantification were set to zero, and zero values were excluded from those geometric summaries. The numerical primary results are not reported in the registry record.

The safety summaries list 0 serious adverse events and 0 deaths in each group. Other adverse events were reported for 3 participants with normal hepatic function and 4 participants with moderate hepatic impairment. These counts are descriptive; the registry information available does not report a statistical comparison of safety outcomes.