ABSTRACT
In accordance with the Centers for Disease Control and Prevention recommendations, pregnant women and those with a recent pregnancy (i.e., lactating) are considered at high risk of developing severe COVID‐19 and qualify for treatment with nirmatrelvir/ritonavir. However, clinical data are lacking in this population because breastfeeding women were excluded from the nirmatrelvir/ritonavir clinical development program and pivotal Phase 2/3 studies. We report findings from a prospective Phase 1 trial (NCT05441215) designed and conducted in accordance with the US Food and Drug Administration guidance on clinical lactation studies that evaluated the pharmacokinetics and safety of multiple oral doses of nirmatrelvir/ritonavir in healthy lactating women using paired breast milk and maternal plasma data. Eight participants were enrolled and completed the study. After administration of nirmatrelvir/ritonavir 300 mg/100 mg to steady‐state, the concentrations of both nirmatrelvir and ritonavir in breast milk were consistently lower than maternal plasma. Based on standard infant breast milk consumption (150 mL/kg/day), the mean absolute daily doses of nirmatrelvir and ritonavir that an infant would receive were 0.1595 and 0.0057 mg/kg/day, respectively, representing 1.8% and 0.19% of the bodyweight‐normalized maternal dose. All treatment‐emergent adverse events were mild to moderate in severity. No deaths, serious or severe adverse events, dose reductions, interruptions, or discontinuations were reported. In conclusion, nirmatrelvir/ritonavir 300 mg/100 mg was safe and well tolerated in healthy lactating women, with infant exposure considered to be low and well within the acceptability criteria of < 10% of the body weight‐normalized maternal dose.
Keywords: healthy subjects, infectious disease, lactation, pharmacokinetics, Phase I, ritonavir
Study Highlights
- What is the current knowledge on the topic?
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○In accordance with the US Centers for Disease Control and Prevention recommendations, pregnancy and recent pregnancy are regarded as underlying medical conditions associated with a higher risk of developing severe COVID‐19. On this basis, breastfeeding women with COVID‐19 would be eligible for nirmatrelvir/ritonavir treatment; however, there is a lack of clinical and safety data available for the treatment of this population.
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- What question did this study address?
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○This Phase 1 prospective trial used paired plasma and breast milk samples to evaluate the pharmacokinetics and safety of multiple oral doses of nirmatrelvir/ritonavir 300 mg/100 mg in healthy lactating women and the levels of exposure to their infants through breastfeeding.
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- What does this study add to our knowledge?
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○In this study, nirmatrelvir/ritonavir had an acceptable safety profile and was well tolerated in healthy lactating women. Nirmatrelvir/ritonavir was transferred to breast milk in quantities expected to be safe for their infants, well below the US National Institutes of Health acceptability threshold of 10% bodyweight‐normalized maternal dose, supporting the overall favorable benefit–risk profile of nirmatrelvir/ritonavir in lactating women.
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- How might this change clinical pharmacology or translational science?
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○Very few lactation studies are conducted during drug development because of safety and ethical concerns. Our prospective pharmacokinetics and safety analysis, conducted in accordance with US Food and Drug Administration guidance on clinical lactation studies, successfully evaluated the potential risk to breastfed infants from drug exposure and could pave the way for larger cohort studies in this population.
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1. Introduction
Human milk provides a vital source of nutrients, hydration, and immunologic protection for infants. The American Academy of Pediatrics and the World Health Organization recommend exclusive breastfeeding, when possible, for at least the first 6 months of life and then continued breastfeeding, as appropriate, until the child is 2 years of age or older [1, 2, 3]. However, because of safety and ethical concerns, exclusion of pregnant and lactating women from drug development trials is commonplace, and very few lactation studies have been conducted during the drug development process [4, 5]. Safety concerns are driven by the risk of significant secondary exposure to the infant through breast milk or, conversely, for anti‐infectives, below‐target exposure, increasing the risk of selection for drug‐resistant organisms in instances where the infant acquires the infection for which the mother is being treated [5]. The potential for a safety risk to the infant without any direct benefit also raises ethical concerns regarding the conduct of lactation studies [5]. Historically, much of the evidence on lactation has been derived from exploratory studies, with very few dedicated investigational trials, leading to a scarcity of evidence for the transfer of drugs through breast milk. Therefore, prescribing practices have been challenging in this population [5]. Furthermore, several models for predicting the excretion of drugs have not been reliably predictive [6].
The 2007 US Food and Drug Administration (FDA) Amendments Act and the 2015 Pregnancy and Lactation Labeling Rule were significant turning points, enabling the FDA to request studies in pregnant and lactating women [7]. In 2019, to facilitate informed, evidence‐based decisions on drug safety by lactating women and their healthcare providers, the FDA encouraged sponsors to undertake clinical lactation studies in accordance with the newly published guidance [8]. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use published the E21 final concept paper in 2023, providing a globally accepted, practical framework for best practices in the conduct of clinical trials with pregnant and breastfeeding individuals, signaling the increasing global importance of clinical lactation studies [9].
Guidance published in 2024 by the US Centers for Disease Control and Prevention (CDC) advised mothers with suspected or confirmed COVID‐19 to continue to breastfeed when possible because evidence indicated that SARS‐CoV‐2 was not transmitted in breast milk [10]. However, those who are currently or recently pregnant (i.e., lactating) are regarded by the CDC as being at high risk of developing severe COVID‐19 [11]. Pregnant women with COVID‐19 are more likely to be diagnosed with hypertension, preeclampsia, and infections requiring antibiotics and are at an increased risk of admission to intensive care compared with pregnant women without COVID‐19 [12, 13]. Severe COVID‐19 infection in pregnancy is also associated with increased risk of preterm delivery, higher rates of stillbirth, and increased likelihood of admission of the infant to neonatal care compared with infants born to mothers with mild to moderate COVID‐19 in pregnancy [13, 14].
The oral antiviral SARS‐CoV‐2 main protease inhibitor nirmatrelvir in combination with the pharmacokinetic (PK) enhancer ritonavir (nirmatrelvir/ritonavir; Paxlovid, Pfizer Inc, New York, NY, USA) is indicated for the treatment of mild to moderate COVID‐19 in adults at high risk of progression to severe COVID‐19, including hospitalization or death [15]. In accordance with CDC recommendations, pregnant women and those with a recent pregnancy are considered at high risk of developing severe COVID‐19 and qualify for treatment with nirmatrelvir/ritonavir [11, 15]. In 2021, 84.1% of mothers in the United States breastfed their infant at any time, and 59.8% were continuing to breastfeed 6 months after birth [16]; it could therefore be assumed that some women who had COVID‐19 during pregnancy or soon after delivery received nirmatrelvir/ritonavir and breastfed their infants.
Breastfeeding women were excluded from the nirmatrelvir/ritonavir clinical development program [17, 18, 19, 20, 21, 22, 23] and pivotal Phase 2/3 studies [24, 25, 26], resulting in a lack of clinical data in breastfeeding women. Consequently, a lack of safety information and unknown risks to the infant have been cited by lactating women eligible for nirmatrelvir/ritonavir as a reason for declining treatment [27].
In the current study, we undertook a prospective Phase 1 trial, in accordance with recent FDA guidance for studies of lactating women [8], to determine the amount of nirmatrelvir/ritonavir distributed into breast milk and maternal plasma after administration of multiple oral doses in healthy lactating women and to assess the potential risk to infants from exposure to nirmatrelvir/ritonavir during breastfeeding.
2. Materials and Methods
2.1. Study Overview and Participants
This was an open‐label, Phase 1, multiple‐dose study (NCT05441215) conducted from December 12, 2022 to December 15, 2023, evaluating the PK and safety of oral nirmatrelvir/ritonavir in healthy lactating women using paired breast milk and maternal plasma data. Participants were screened for eligibility ≤ 28 days before treatment and were included in the study if they were actively breastfeeding or expressing breast milk and were willing to temporarily discontinue breastfeeding for a total of 4.5 days. As per FDA guidance, participants had to agree to temporarily pump and discard breast milk to avoid exposing their infant to the investigational drug [8]. Individuals were required to be ≥ 12 weeks postpartum, confirmed as not pregnant (serum or urine test), and aged 18–55 years. In addition, they must have had a bodyweight > 50 kg and a body mass index (BMI) ≥ 17.5 kg/m2. Infants of mothers included in the study had to be able to feed successfully from a bottle or other age‐appropriate alternative feeding method before the start of the study and tolerate infant formula if there was not a sufficient supply of stored breast milk for the duration of the study when nursing was restricted. Participants were excluded if they tested positive for SARS‐CoV‐2 infection at screening or Day −1 or were unable to express ≥ 14 mL of breast milk over a 2 h period using an electric breast pump before the dose on Day 1. A full list of the inclusion and exclusion criteria is provided in the Supporting Information.
2.2. Study Design
The protocol and other relevant study documents were approved by the institutional review board (Comité d'Ethique hospitalo‐facultaire Erasme‐ULB [021/406]; approval: October 3, 2022) at the participating investigator's center; participants provided informed consent and were informed that participation was voluntary. The study was conducted in accordance with FDA guidance on clinical lactation studies [8], the principles of the Declaration of Helsinki, the International Conference on Harmonization‐Good Clinical Practice, and all applicable local regulations.
Approximately eight participants were planned for enrollment; if participants withdrew or were unable to express breast milk, additional participants could be recruited. Eligible participants reported to the clinical research unit on Day 1 for COVID‐19 testing and breast milk collection. On Day −1, each enrolled participant took study medication (two nirmatrelvir 150 mg tablets [Pfizer Inc] and one ritonavir 100 mg tablet [NORVIR; AbbVie Deutschland GmbH & Co., KG, Germany]) orally at approximately 8:00 a.m. and 8:00 p.m. (±2 h), with a third dose in the morning on Day 2 (for a total of three doses representing steady‐state dosing). Nirmatrelvir and ritonavir were administered simultaneously within no more than 5 min of each other, starting with nirmatrelvir, with ambient temperature water (240 mL; an additional 50 mL was provided if needed). Participants swallowed all tablets whole without manipulation or chewing before swallowing. Individuals were not permitted to breastfeed their infant for a total of 4.5 days (approximately 108 h) from the evening of the day before the first dose, throughout the dosing period, and for 72 h after the final dose, and were required to plan for when breastfeeding was prohibited (e.g., express sufficient milk in advance or obtain formula). Samples for PK evaluation were collected after participants consumed a high‐fat (approximately 50% of the total caloric content of the meal), high‐calorie (approximately 800–1000 cal) meal so that nirmatrelvir/ritonavir exposure could be estimated in the fed state. The fed state was used as a conservative estimate of maternal and infant exposure because the exposure of nirmatrelvir/ritonavir is enhanced when administered with food (approximately a 1.2‐fold increase in maximum observed concentration [C max]) [17]. Breast milk was collected using an electric breast pump over 2 h intervals on Day ‐ 1 and on Day 1 before the first dose and for 48 h after the Day 2 (third) dose over the following intervals: 0–2, 2–4, 4–8, 8–12, 12–24, 24–32, 32–40, and 40–48 h. Breast milk, including foremilk and hindmilk, collected from both breasts, was pooled, and the entire volume was collected for each sample time interval. Blood samples (4 mL) for PK evaluation were collected before the third dose, then at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18, 24, 32, 40, and 48 h after the third dose. Participant health was assessed by physical examination (including supine 12‐lead electrocardiogram [ECG]) and laboratory assessments during screening. Vital signs were assessed during screening, before the first and third dose, and at 12 and 48 h after administration of the first and last dose, respectively. A safety follow‐up call to participants was scheduled approximately 28–35 days from administration of the final dose (Figure S1).
2.3. Study Endpoints
PK endpoints were assessed after multiple oral twice‐daily (BID) administrations with nirmatrelvir/ritonavir. Primary endpoints were nirmatrelvir breast milk PK parameters (C max, time to reach C max [t max], area under the concentration‐time profile [AUC] during the dosing interval [i.e., 0–12 h; AUCtau], terminal half‐life [t 1/2], average steady‐state plasma concentration [C av], amount excreted in breast milk over the 12 h dosage interval, percentage of the dose excreted in breast milk over the 12h dosage interval, and breast milk clearance [CLbm]).
Secondary PK endpoints were ritonavir breast milk PK parameters and nirmatrelvir and ritonavir maternal plasma PK parameters. Breast milk and maternal plasma nirmatrelvir and ritonavir PK parameters, as well as the parameters used for estimation of absolute and relative infant dose, are presented (Table S1). Safety was assessed via secondary endpoints: treatment‐emergent adverse events (TEAEs), clinical laboratory tests, vital signs, physical examination, and ECGs in lactating women.
2.4. PK Evaluation
PK parameters in breast milk and maternal plasma were analyzed using standard noncompartmental methods (Supporting Information). Analysis of plasma samples for nirmatrelvir and ritonavir concentrations has been described previously [22].
Nirmatrelvir and ritonavir PK parameters for breast milk and maternal plasma were derived using actual PK sampling times when available; otherwise, nominal times were used. For breast milk PK parameters, the midpoint of the sampling time interval was used. Plots of AUC, C max, and C av were presented for each analyte, comparing PK parameters in breast milk versus maternal plasma.
2.5. Safety Analyses
The investigator actively detected and recorded adverse events (AEs) from the time of informed consent to 28–35 days after the final dose. After an AE was reported, participants were proactively followed by investigators at subsequent visits until the event resolved, stabilized, or was otherwise explained, or the participant was lost to follow‐up. AEs were classified and coded using the Medical Dictionary for Regulatory Activities v26.1.
2.6. Statistical Analyses
All participants who received ≥ 1 dose of nirmatrelvir/ritonavir and for whom ≥ 1 breast milk or plasma concentration and ≥ 1 PK parameter were reported were included in the analysis population. The safety population included all participants who received ≥ 1 dose of nirmatrelvir/ritonavir. No formal hypothesis testing was conducted; PK parameters were summarized using descriptive statistics.
3. Results
3.1. Study Participants
Eight participants were enrolled; all participants completed the study and were included in the PK and safety analysis populations. All participants were female and White, and none were Hispanic or Latino. The median (range) age was 33.5 (22–43) years, and the median (range) BMI was 23.6 (19–38) kg/m2. The median (range) duration of the current lactation period was 28.5 (13–78) weeks (Table 1).
TABLE 1.
Demographic and baseline characteristics.
| Characteristic | All participants (N = 8) |
|---|---|
| Age, years, n (%) | |
| < 18 | 0 |
| 18–25 | 1 (12.5) |
| 26–35 | 4 (50.0) |
| 36–45 | 3 (37.5) |
| > 45 | 0 |
| Median (range) | 33.50 (22–43) |
| Sex, female, n (%) | 8 (100.0) |
| Race, White, n (%) | 8 (100.0) |
| Ethnicity, not Hispanic or Latino, n (%) | 8 (100.0) |
| Weight (kg) | |
| Median (range) | 61.58 (56–99) |
| Body mass index (kg/m2) | |
| Median (range) | 23.55 (19–38) |
| Duration of current lactation (weeks) | |
| Median (range) | 28.50 (13–78) |
3.2. PK of Nirmatrelvir
After administration of three oral doses of nirmatrelvir/ritonavir 300 mg/100 mg BID over 2 days to healthy lactating women, the nirmatrelvir concentrations in breast milk were consistently lower than maternal plasma concentrations, with a longer arithmetic mean t 1/2 of approximately 7.2 h for plasma compared with 4.4 h for breast milk (Figure 1A; Table 2). The median (range) t max was similar for breast milk (3.22 [3.22–6.22] h) and plasma (3.56 [1.08–4.07] h). Exposure of nirmatrelvir, based on the geometric mean C max, C av, and AUCtau, was approximately four‐fold lower in breast milk than in plasma (Figure 2A; Table 2). C max and AUCtau values in breast milk expressed as a percentage of values in plasma were 26.9% and 26.0%, respectively. The geometric mean (geometric percentage coefficient of variation [COV]) CLbm of nirmatrelvir was 0.007641 (26) L/h, and the geometric mean daily amount excreted in breast milk was 0.7520 (45) mg, which was 0.13% of the administered daily maternal dose of nirmatrelvir 600 mg (i.e., 300 mg BID). The geometric mean (COV) absolute daily dose that an infant would receive based on C av, the milk‐to‐plasma ratio for AUCtau (MPAUCtau), and a standard infant breast milk consumption of 150 mL/kg/day [8] was 0.1595 (36) mg/kg/day, which represented 1.8% of the bodyweight‐normalized maternal dose (Table 2). When assuming a higher (i.e., more conservative, for risk assessment) infant breast milk consumption of 200 mL/kg/day, the estimated dose that the infant would receive was 0.207 mg/kg/day, representing 2.3% of the bodyweight‐normalized maternal dose for nirmatrelvir.
FIGURE 1.
Median nirmatrelvir (A) and ritonavir (B) plasma and breast milk concentration‐time profiles on Day 2 after administration of multiple oral doses of nirmatrelvir/ritonavir 300 mg/100 mg BID. BID, twice daily.
TABLE 2.
Plasma and breast milk PK parameters after administration of multiple oral doses of nirmatrelvir/ritonavir, 300 mg/100 mg BID.
| Parameter (unit) | Nirmatrelvir (n = 8) | Ritonavir (n = 8) |
|---|---|---|
| Plasma | ||
| AUCtau (ng×h/mL) | 49,190 (21) | 6893 (31) |
| C max (ng/mL) | 7080 (17) | 1228 (48) |
| t max (h) | 3.56 (1.08–4.07) | 4.03 (2.00–6.00) |
| t 1/2 (h) | 7.180 ± 1.3299 | 5.190 ± 0.79075 |
| C min (ng/mL) | 1240 (32) | 136.9 (20) |
| Breast milk | ||
| AUCtau (ng×h/mL) | 12,770 (36) | 456.8 (47) |
| C max (ng/mL) | 1904 (33) | 71.99 (66) |
| t max (h) | 3.22 (3.22–6.22) | 3.17 (3.17–6.17) |
| t 1/2 (h) | 4.455 ± 0.68964 | NR a |
| Aetaubm (mg) | 0.3758 (45) | 0.01354 (56) |
| Aetaubm (%) | 0.1253 (45) | 0.01354 (56) |
| CLbm (L/h) | 0.007641 (26) | 0.001966 (30) |
| Ae24bm (mg) | 0.7520 (45) | 0.02709 (56) |
| MPAUCtau | 0.2596 (26) | 0.06626 (21) |
| MPCmax | 0.2689 (23) | 0.05860 (35) |
| BWNID (mg/kg/day) | 0.1595 (36) | 0.005709 (47) |
| BWNMD (mg/kg/day) | 8.969 (22) | 2.990 (23) |
| BWNIDPCM (%) | 1.779 (27) | 0.1910 (42) |
Note: Data are geometric mean (geometric % coefficient of variation), except for the median (range) for t max, and the arithmetic mean ± SD for t 1/2.
Abbreviations: Ae24bm, daily (24h) amount excreted in breast milk; Aetaubm, amount excreted in breast milk over the dosing interval (12 h); AUCtau, area under the concentration‐time profile from time zero to the end of the dosing interval; BID, twice daily; BWNID, bodyweight‐normalized infant dose; BWNIDPCM, infant dose expressed as a percentage of bodyweight‐normalized maternal dose; BWNMD, bodyweight‐normalized maternal dose; CLbm, breast milk clearance; C max, maximum observed concentration; C min, minimum observed concentration over the dosing interval; MPAUCtau, milk‐to‐plasma ratio for AUCtau; MPCmax, milk‐to‐plasma ratio for C max; N, total number of participants in the treatment group in the indicated population; NR, not reported; PK, pharmacokinetic; t 1/2, terminal half‐life; t max, time to reach C max.
All participants in each treatment group contributed to summary statistics except for ritonavir t 1/2 in breast milk, which was based on N = 1.
FIGURE 2.
Plasma and breast milk AUCtau, C max, and C av on Day 2 for nirmatrelvir (A) and ritonavir (B) after administration of multiple oral doses of nirmatrelvir/ritonavir 300 mg/100 mg BID. Data are individual (star) and geometric mean (open circle) values; the box plot provides median and 25%/75% quartiles with whiskers to the last point within 1.5 times the interquartile range. AUCtau, area under the concentration‐time profile from time zero to the end of the dosing interval; BID, twice daily; C av, average steady‐state plasma concentration; C max, maximum observed concentration.
3.3. PK of Ritonavir
Breast milk concentrations of ritonavir were also much lower than maternal plasma concentrations (Figure 1B). For all participants, the geometric mean (COV) C max and C av were lower in breast milk (71.99 [66] ng/mL and 38.08 [47] ng/mL, respectively) than in plasma (1228 [48] ng/mL and 574.5 [31] ng/mL; Figure 2B, Table 2). The median (range) t max was similar for breast milk (3.17 [3.17–6.17] h) and plasma (4.03 [2.00–6.00] h). The geometric mean C max and AUCtau values of ritonavir in breast milk were 6% and 7%, respectively, of those for plasma. The geometric mean (COV) CLbm of ritonavir was 0.001966 (30) L/h, and the geometric mean daily amount excreted in breast milk was 0.02709 (56) mg, which was 0.014% of the administered daily maternal dose of ritonavir 200 mg (i.e., 100 mg BID). The geometric mean (COV) absolute daily dose that an infant would receive based on C av, the MPAUCtau, and a standard infant breast milk consumption of 150 mL/kg/day [8] was 0.0057 (47) mg/kg/day, which represented 0.19% of the bodyweight‐normalized maternal dose (Table 2). When assuming a higher (i.e., more conservative) infant breast milk consumption of 200 mL/kg/day, the dose that the infant would receive was 0.0076 mg/kg/day, representing 0.25% of the bodyweight‐normalized maternal dose for ritonavir.
3.4. Safety
Overall, 22 TEAEs were reported by eight participants (Table S2), of which 13 were deemed related to treatment. The most frequently reported treatment‐related TEAE was dysgeusia, which occurred in seven participants (87.5%). All TEAEs were mild to moderate in severity. No deaths, serious or severe AEs, or TEAEs leading to dose reductions, interruptions, or discontinuations were reported (Table 3). No clinically meaningful laboratory tests or vital signs were reported. Urine abnormalities were reported by four participants (urine bilirubin ≥ 1, n = 1; leukocyte esterase ≥ 1, n = 2; urine hemoglobin ≥ 1 and leukocyte esterase ≥ 1, n = 1). A single participant reported supine systolic blood pressure < 90 mmHg, which was deemed not related to treatment.
TABLE 3.
Summary of AEs in the safety analysis set.
| Adverse event, n (%) | Nirmatrelvir/ritonavir 300 mg/100 mg (N = 8) |
|---|---|
| Participants with TEAEs (all causalities) | 8 (100) |
| Participants with TEAEs (treatment‐related) | 8 (100) |
| Treatment‐emergent SAEs | 0 |
| Severe TEAEs | 0 |
| Discontinuations/dose reductions | 0 |
| Deaths | 0 |
| Participants with any treatment‐related AE a | |
| Nervous system disorders | |
| Dysgeusia | 7 (87.5) |
| Headache | 2 (25.0) |
| Dizziness | 1 (12.5) |
| Gastrointestinal disorders | |
| Nausea | 1 (12.5) |
| Reproductive system/breast disorders | |
| Dysmenorrhea | 1 (12.5) |
| Heavy menstrual bleeding | 1 (12.5) |
Abbreviations: AE, adverse event; SAE, serious adverse event; TEAE, treatment‐emergent adverse event.
Participants were only counted once per treatment per event. Includes data up to 28–35 days after the last dose of the study drug.
4. Discussion
This study presents, to date, the only prospective PK analysis of breast milk with paired maternal plasma data obtained from lactating mothers after administration of nirmatrelvir/ritonavir 300 mg/100 mg, as well as safety data to evaluate the potential risk to infants from drug exposure. The geometric mean infant daily doses of nirmatrelvir and ritonavir in breast milk, expressed as a percentage of the bodyweight‐normalized maternal dose after administration of three doses of nirmatrelvir/ritonavir 300 mg/100 mg, were 1.8% and 0.19%, respectively. While the current study was ongoing, Dai et al. also reported low infant exposure in milk samples from eight mothers who received nirmatrelvir/ritonavir in a cross‐sectional, descriptive study [28]. In that study, the estimated relative infant doses were 1.43% and 0.19% for nirmatrelvir and ritonavir, respectively [28]. The similarity in the relative infant dose of nirmatrelvir and ritonavir in two independent studies in different settings provides validity that the exposure of nirmatrelvir and ritonavir in infants is low and considered relatively safe, based on the US National Institute of Health (NIH) acceptability criteria of < 10% bodyweight‐normalized maternal dose [29].
Ritonavir excretion in breast milk has been reported in studies of mothers with HIV. In samples from 30 mother–infant pairs after a maximum of 28 weeks of ritonavir treatment (administered as two tablets of lopinavir 200 mg/ritonavir 50 mg, BID), most breast milk and maternal plasma samples contained ritonavir at a median concentration of 79 and 364 ng/mL (reported as 0.079 and 0.364 μg/mL), respectively [30]. The median ritonavir AUCs from time 0–6 h in breast milk and maternal plasma were 0.490 and 2.30 μg×h/mL, respectively [30]. In a separate study, a subgroup of nine women who tested positive for HIV received ritonavir 100 mg BID. In these women, the median ritonavir concentrations in breast milk and maternal serum (with a median interval of 4.5 h between dosing and sample collection across the whole study population) were 79 and 422 ng/mL, respectively, and the infant's median ritonavir concentration in serum was 7 ng/mL [31]. Similarly, mean ritonavir C av levels of 38.08 ng/mL in breast milk and 574.5 ng/mL in plasma were observed in this study.
Our study was designed and conducted in accordance with FDA guidance on clinical lactation studies [8]. Because there were no safety data in infants available before the commencement of this study, a mother–infant paired study that assesses drug concentrations in infants was not appropriate [8]. To keep infants safe from drug exposure, it was mandated that mothers discard milk for 4.5 days (approximately 108 h) from the evening before the first dose of study drug through 72 h after the last dose; a 4.5 day breastfeeding discontinuation period was selected based on the known half‐lives of nirmatrelvir (6.05 h) and ritonavir (6.15 h) when given in combination to healthy individuals [8, 15]. A three‐dose longitudinal design was selected to study the breast milk and maternal plasma PK of nirmatrelvir/ritonavir exposure under steady‐state conditions (with steady‐state achieved by Day 2 of dosing), while also ensuring that breastfeeding interruption was minimized. Milk sampling was conducted in accordance with FDA guidance [8]; to avoid inclusion of colostrum or transitional milk, sampling took place at ≥ 12 weeks postpartum (after development of mature breast milk), an electric pump was used to ensure efficient milk extraction, and the entire volume of breast milk was collected at the end of each sampling period. PK samples were collected after participants received a high‐fat meal to evaluate breast milk exposure in the fed state to account for increased nirmatrelvir exposure observed after administration with a high‐fat meal [17].
Both nirmatrelvir and ritonavir transferred into breast milk, with similar findings based on a standard infant breast milk consumption of 150 mL/kg/day [8] and also when assuming a higher (i.e., more conservative) infant breast milk consumption of 200 mL/kg/day, with levels for both well below the NIH acceptability criteria of 10% bodyweight‐normalized maternal dose [29]. Studies evaluating levels of ritonavir in breast milk are scarce; as described above, Corbett et al. reported an average concentration of 79 ng/mL (reported as 0.079 μg/mL) ritonavir in the breast milk of mothers with HIV collected over 6 h [30]. However, participants received lopinavir/ritonavir; therefore, direct comparisons with our study cannot be made, as the PK of ritonavir could be impacted by the differing antiviral drugs and patient populations.
Our findings for breast milk samples were comparable with Dai et al., who reported a mean infant dose of 0.054 mg/kg/12 h (equivalent to 0.108 mg/kg/day) and 0.0024 mg/kg/12 h (equivalent to 0.0048 mg/kg/day) for nirmatrelvir and ritonavir [28]. Nonetheless, our robust, prospective study in healthy volunteers with paired milk and plasma sampling offers significant advantages over the findings reported by Dai et al., which were opportunistic, descriptive, and retrospective; used repository milk samples collected up to 12 h from women prescribed nirmatrelvir/ritonavir in accordance with clinical care; and did not collect plasma samples from the mothers. AEs in this study were also self‐reported.
There are several limitations to our study. The sample size of eight women was relatively small, limiting the ability to generalize these findings to the entire population. Furthermore, our study was not designed to assess the impact of nirmatrelvir/ritonavir on milk production, nor did it include infant safety data or long‐term follow‐up of the mothers beyond 35 days after administration of the final dose of nirmatrelvir/ritonavir.
In conclusion, this prospective Phase 1 study, conducted in accordance with FDA guidance, demonstrated that nirmatrelvir/ritonavir was safe and welltolerated in healthy lactating women and transferred to breast milk in quantities expected to be relatively safe for their infants, supporting the favorable benefit–risk profile of nirmatrelvir/ritonavir in the lactating patient population.
Author Contributions
All authors wrote the manuscript. J.G., N.C., K.M., J.K.M., J.H., and R.S.P.S. designed the research. H.S. and J.K.M. performed the research. K.P., K.M., and H.S. analyzed the data.
Funding
This study was sponsored by Pfizer Inc.
Conflicts of Interest
All authors are or were employees of Pfizer Inc and may hold Pfizer stock.
Supporting information
Table S1: Definitions of plasma and breast milk nirmatrelvir and ritonavir PK parameters.
Table S2: Complete listing of all TEAEs by study participant.
Figure S1: Study design.
Acknowledgments
Medical writing support was provided by James Currie, PhD, and Nazneen Qureshi, PhD, Conf of ICON (Blue Bell, PA, USA) and was funded by Pfizer Inc.
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related, individual, de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Definitions of plasma and breast milk nirmatrelvir and ritonavir PK parameters.
Table S2: Complete listing of all TEAEs by study participant.
Figure S1: Study design.
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related, individual, de‐identified participant data. See https://www.pfizer.com/science/clinical‐trials/trial‐data‐and‐results for more information.