Pharmacokinetics of HIV-integrase inhibitors

Pharmacokinetics of HIV-integrase inhibitors is influenced by physiological changes occurring during pregnancy. (1) Very little information is available regarding altered pharmacokinetics in pregnant and required dosage adjustments of these drugs. (2) Especially for new developed drugs, such as HIV-integrase inhibitors, a knowledge gap exists on the influence of pregnancy-related mechanisms on altered maternal pharmacokinetics, drug efficacy and adverse effect profiles. Mechanistic-based approaches on these aspects can attribute to improved HIV-treatment strategies and is useful to be implemented in new perinatal HIV guidelines. (3) This may inform perinatal HIV guidelines for drugs with limited data available in pregnancy.

Currently, the most recent US Department of Health and Human Services (DHHS) perinatal guidelines recommend to add a boosted protease inhibitor (atazanavir/ritonavir or darunavir/ritonavir) or an HIV-integrase inhibitor (raltegravir) to the backbone consisting of two nucleoside reverse transcriptase inhibitors (NRTIs). (4) HIV-integrase inhibitors target the HIV integrase enzyme, responsible for incorporation of pro-viral HIV-1 DNA in to the host cell genome. HIV-integrase inhibitors have gained a leading position in treating HIV-1 because of increased viral suppression, less drug-drug interactions and fewer side-effects. If safety of the HIV-integrase inhibitor dolutegravir in pregnant women is confirmed by ongoing studies, it might even become the first option in World Health Organization (WHO) guidelines. (5) Therefore, HIV-integrase inhibitors are expected to become first-line therapy in sub-Saharan Africa and other HIV-endemic regions for which adequate knowledge on pharmacokinetics in pregnancy is an important condition. (6) Each individual HIV-integrase inhibitor possesses unique pharmacokinetic and pharmacodynamic profiles enabling physicians to prescribe patient-tailored drugs to HIV-infected pregnant women. (7)

Exposure to antiretroviral drugs is not tested during clinical development in pregnant women. However, after approval these drugs are also prescribed for pregnant women. To overcome this gap of knowledge, it is important to elucidate their mechanistic basics and clinical pharmacokinetics. Moreover, a detailed overview of the pharmacokinetics and mechanistics of HIV-integrase inhibitors during pregnancy can provide novel insights in the development of HIV-therapy. This review therefore focuses on the mechanisms, clinical implications and knowledge gaps of pharmacokinetic changes of HIV-integrase inhibitors during pregnancy.

1. Altered pharmacokinetics in pregnancy

In this section we will discuss to what extent absorption, distribution, metabolism, elimination of HIV-integrase inhibitors is altered during pregnancy.

2.1 Drug absorption

Drug absorption of HIV-integrase inhibitors can be altered because of many physiological changes that occur during pregnancy, such as an increased gastric pH or reduced intestinal motility. (3) These factors are important for orally administered drugs, such as HIV-integrase inhibitors, which show a great variability in drug absorption. (8) Bioavailability of HIV-integrase inhibitors is affected by both the first-pass effect as well as the amount of drug absorbed across the intestinal epithelia. Due to an increase in mucus secretion but a decreased gastric acid production, gastric pH is increased during pregnancy. (9) As a result, ionization of weak acids such as HIV-integrase inhibitors can be increased, but its absorption reduced. (10) Thus, drug absorption of HIV-integrase inhibitors as well as oral bioavailability could be diminished by decreased gastric acid secretion and a slower intestinal motility. In contrast, because of increased intestinal blood flow and cardiac output during pregnancy, drug absorption of HIV-integrase inhibitors can be overall increased. There is also a clear increase in renal drug transporter activity during pregnancy. Pregnancy leads to increased activity of P-glycoprotein (P-gp), organic anion transporter 1 (OAT1) and organic cation transporter 2 (OCT2). These processes may result in lower HIV-integrase inhibitor concentrations in the circulation. (11) However, changes in intestinal P-gp expression did not result in significantly altered absorption of elvitegravir. (12) More confirmatory evidence is necessary to validate these findings. (8)

2.2 Drug distribution

The most important parameter which indicates how extensively a systemic dose of medication is dispersed throughout the human body is the volume of distribution (Vd). During pregnancy, several hemodynamic changes result in augmented plasma volume up to 50% and decreased plasma protein binding, which can be of influence on the Vd of HIV-integrase inhibitors. (3) Measuring the Vd before, during and after pregnancy enables physicians to adjust the dose of HIV-integrase inhibitors for an optimal therapeutic concentration. Protein binding during pregnancy can also be important to account for considering the different HIV-integrase inhibitors. For example, a case report found that the fraction unbound (fu) of elvitegravir was 0.3% during both the third trimester and 5 weeks postpartum, which was lower than fu values measured in a non-pregnant HIV-infected population. As a consequence, the unbound Cmin of elvitegravir was < 0.5 ng/mL and thus suboptimal. Suboptimal fu values and Cmin of HIV-integrase inhibitors lead to lower 90% effective response ratios (EC90) which may result in MTCT of HIV or HIV-resistance. (13) In non-pregnant HIV-infected patients, both dolutegravir and elvitegravir are >99% bound to both albumin and alpha-1-acid glycoprotein, while raltegravir is 76-83% bound to albumin. (12) Altered albumin levels in pregnant women are therefore mainly relevant for pharmacokinetics of dolutegravir and elvitegravir. Because serum albumin and alpha 1 acid glycoprotein concentrations decrease up to respectively 31% and 19% in the final phase of pregnancy, this will affect unbound fraction of HIV-integrase inhibitors during pregnancy.(14) Because the unbound fraction of HIV-integrase inhibitors may be altered during pregnancy, it is important to measure free concentrations of HIV-integrase inhibitors. (15)

2.3 Drug metabolism

HIV-integrase inhibitors are converted into inactive metabolites principally by the liver. Metabolic enzyme activity can be influenced by several factors such as gender, ethnicity, age and enzyme polymorphisms. Uridine diphosphate glucuronosyltransferase (UGT) and Cytochrome P450 (CYP) are the most important classes of metabolic enzymes involved in drug metabolism of HIV-integrase inhibitors.(3) Dolutegravir and raltegravir are primarily metabolized by UGT iso-enzyme UGT1A1, while elvitegravir is partly metabolized by this enzyme.(12) It is therefore important to account for this altered UGT1A1 activity to prevent suboptimal ARV levels in pregnant HIV-patients. Considering CYP metabolism, elvitegravir is primarily metabolized by CYP3A4, while dolutegravir and raltegravir are partly metabolized by this CYP iso-enzyme. CYP3A iso-enzymes are also induced during pregnancy through increased cortisol concentrations primarily,(16) but estradiol and progesterone may also contribute.(17) Moreover, several studies which focused on HIV-protease inhibitors suggest that CYP3A4 activity is increased during pregnancy. (18, 19) This may also count for HIV-integrase inhibitors resulting in an increased conversion of dolutegravir and elvitegravir into inactive metabolites during pregnancy. However, these studies had large interindividual variability and small sample sizes.

2.4 Drug elimination

HIV-integrase inhibitors were mostly excreted in faeces, followed by urine. (12) The untransformed drug was the most frequent entity in plasma, whereas inactive glucuronides of dolutegravir and raltegravir were primarily recovered in urine. Renal excretion of drugs is increased in pregnant women, which may be a result of increased renal secretion via transporters or because of an increased glomerular filtration rate. (3) During the third trimester, renal secretion clearance which is mediated by P-glycoprotein and organic cation transporters, is increased during pregnancy.(20, 21) It is unclear in literature whether pregnancy leads to altered elimination half-life of HIV-integrase inhibitors. The IMPAACT group (22) found decreased elimination half-life of dolutegravir during both the second and third trimester compared to postpartum. Blonk et al(23) did not find alterations in elimination half life of raltegravir between HIV-infected pregnant women during third trimester and postpartum. Raltegravir is primarily metabolized by UGT1A1 and increased progesterone levels in pregnant women may result in increased clearance of UGT1A1 substrates. This hypothesis was also supported by Blonk et al(23). Pregnancy induces UGT1A1 activity resulting in increased glucuronidation and thus inactivation of HIV-integrase inhibitors.(24) Two case reports on dolutegravir(25) and elvitegravir(26) found a shorter half life of both drugs in the third trimester compared to postpartum in HIV-infected pregnant women. This would support the assumption of increased UGT1A1 and CYP3A4 activity responsible for the conversion of both drugs into inactive metabolites.

A mice study found elevated levels of serum bile acids during the end of pregnancy caused by downregulation of drug uptake transporters. This could also lead to increased excretion of HIV-integrase inhibitors. Apparently, the liver reduces hepatobiliary excretion at the end of pregnancy in order to compensate for increased hepatic perfusion or to reduce hepatobiliary excretion. (27)

2. Altered PK of HIV-integrase inhibitors

HIV integrase inhibitors are more often implemented as third drug in the cART regimen in pregnant women. This group of drugs has a rapid effect on viral decay which attributes to a high CD4 count recommended by the newest DHHS guidelines. (4, 28) In table 1, an overview of all studies describing altered pharmacokinetics of HIV-integrase inhibitors in pregnant women is presented. In this section the pharmacokinetics of HIV integrase inhibitors in pregnant women will be described.

2.1 PK of cabotegravir

2.2 Dolutegravir

Data on usage of dolutegravir in pregnant women are limited. In non-pregnant HIV patients, dolutegravir is readily absorbed with a median maximum concentration (Cmax) within 2.5h. (29, 30) Exposure to dolutegravir is increased by low-, moderate-, and high-fat meals, although dolutegravir may be taken without regard to food intake. (12) Dolutegravir absorption is impaired by co-administration of drugs containing di- or trivalent cations. This can be overcome by separating the different drugs. After absorption, dolutegravir binds for more than 99% to plasma proteins alpha-1-acid glycoprotein and albumin. (12) Zhang et al(31) combined pharmacokinetic data from three studies on dolutegravir and found an oral clearance of 0.901/L, a volume of distribution (V/F) of 17.41 L and an absorption rate constant of 2.24 h-1.

Rat studies show that dolutegravir is able to cross the placental barrier. Moreover, a recent study (32) developed an ex vivo human cotyledon perfusion model and showed that dolutegravir is able to cross the placental barrier. This study confirms that dolutegravir also crosses the placental barrier in vivo and therefore holds clinical potential for pre-exposure prophylaxis, prevention of MTCT but also risk of toxicity to the newborn. It is primarily metabolized by UGT1A1 and secondly by CYP3A4. Because both these enzymes are up-regulated during pregnancy, metabolization of dolutegravir is possibly increased leading to lower dolutegravir concentrations during pregnancy. To prevent suboptimal dosages as well as toxicity, dosing of dolutegravir needs to be accurate. A recent study from Zhang et al(31) focusing on non-pregnant HIV-infected adults found a lack of PK/PD relationship between any of the efficacy endpoints and dolutegravir exposure, which may be attributable to the high potency of the combination of dolutegravir with two NRTIs. Also no relationship between dolutegravir exposure and safety endpoints was found, except for CRCL and serum creatinine, which were correlated with exposure to dolutegravir. This suggests that dose adjustments for dolutegravir are not needed in renally impared patients. (31)

In table 1, outcomes of a case report(25), a prospective cohort study(33) and a non-randomized open label phase IV study (22) are presented describing pharmacokinetics of dolutegravir in HIV-infected pregnant women. The latter study showed that exposure, Cmin and Cmax were all decreased in the second and third trimester compared to postpartum, whereas CL/F was increased during pregnancy. This study suggested that mainly UGT1A1 activity, induced by increased progesterone levels, and partly induced CYP3A4 activity were responsible for these pharmacokinetic changes. (22)

2.3 PK of elvitegravir

Elvitegravir pharmacokinetics has not yet been extensively evaluated during pregnancy. Therefore, the NHHS guidelines do not recommend to prescribe elvitegravir to HIV-infected pregnant women. (4) In healthy volunteers, elvitegravir was quickly absorbed with a median Cmax between 1.3 and 2.5 h post-dose. Oral bioavailability of elvitegravir is significantly increased after administration with a meal. Both the AUC and Cmax were increased, with 34 and 24% respectively after intake of elvitegravir with a meal. After dosing with food, Cmax was reached in 4-4.5h. Absorption of elvitegravir is significantly decreased if co-administered together with divalent or trivalent cations. Therefore, antacids and multivitamins need to be administered separately from elvitegravir. (12) Pharmacokinetic values for elvitegravir in HIV-infected pregnant women were reported in two case reports(13, 26) and two prospective cohort studies (33, 34). Cmin and half-life (t1/2) were decreased in both cases during the third trimester and in the study from Best et al(34) during the second and third trimester compared to postpartum. Marzolini et al and Best et al found a decreased exposure and Cmax during second or third trimester compared to postpartum. Moreover, it is very hard to draw any conclusion from two case reports containing all available pharmacokinetic data about usage of elvitegravir during pregnancy.

Elvitegravir is co-administered with cobicistat, which is a potent CYP3A4 inhibitor and thus lead to increased exposure of elvitegravir. This is especially relevant during pregnancy, because of the commonly reported decreased cobicistat concentrations during the second and third trimester. Elvitegravir also shows interaction with food resulting in a significantly enhanced oral bioavailability. Both exposure and Cmax of elvitegravir were increased after dosing with food. (35) When elvitegravir is orally administered with food, Cmax is reached in 4-4.5 h. In pregnancy, lower exposure and Cmax of elvitegravir can be expected because of increased levels of estradiol , growth hormones and a subsequent induction of CYP3A4 enzyme activity. (36, 37) This was also observed by Marzolini et al(13) in which decreased exposure, Cmin, Cmax and half-life but increased CL/F were observed in pregnant HIV-infected women using elvitegravir. However, Schalkwijk et al(26) found that exposure was not different in pregnancy compared to postpartum, whereas Cmax was increased compared to postpartum. Half-life and Cmin were also both decreased during third trimester compared to postpartum, which is in line with the study from Marzolini et al(13).

2.4 PK of Raltegravir

Raltegravir shows high pharmacokinetic variability when given either with or without food and is absorbed rapidly, with a Tmax of about 3 h. (12) After absorption, it is 76-83% protein bound, mainly to albumin. (38) After multiple doses of 100-800 mg twice daily, a half-life of 7-12 h was reached. The mean renal clearance of raltegravir, regarding a dose of 400 mg twice daily at steady state, is 3.63 L/h. (12)

The absorption of raltegravir may be decreased during pregnancy resulting in an increased. However, Watts et al(39) found Tmax values of 1.98 h and 2.03 h respectively in third trimester of pregnancy and post-partum among 22 HIV-infected women using raltegravir on an empty stomach. This is not in line with our assumption of delayed absorption due to decreased gastric acid secretion and a slower intestinal motility. This study also found a decreased exposure to raltegravir during pregnancy compared to postpartum which can be caused by increased renal clearance and excretion during pregnancy. Blonk et al(23) also studied pharmacokinetics of raltegravir given with a meal during third trimester and postpartum. This study found decreased exposure to raltegravir and lower trough concentrations during both second and third trimester of pregnancy compared to postpartum, indicating that these pharmacokinetic parameters are affected by pregnancy-related mechanisms. Moreover, patients had relatively high Tmax values in their second trimester (4.0 h) but low values in their third trimester and post-partum of 2.0 and 2.0 h respectively. Hormonal changes and their influence on metabolic enzymes and drug transporters during pregnancy can cause this variation in absorption times. The values for Tmax in the third trimester and postpartum are again lower than Tmax values in non-pregnant HIV-women indicating that reduced exposure to HIV-integrase inhibitors also leads to reduced Tmax in pregnant HIV-infected women. Despite the available data of these two studies, the virological efficacy of raltegravir in these studies and the high degree of interindividual variability, the DHHS guidelines(4) recommend to include raltegravir 400 mg twice daily without dose adjustment in anti-retroviral naïve, pregnant women. (12)

Raltegravir is mainly metabolized by UGT1A1 in humans, whereas UGT1A3 and UGT1A9 play minor roles. Slower clearance of raltegravir can be caused by genetic polymorphisms in UGT1A1 which result in higher plasma concentrations. This increase is not considered clinically significant, also because pregnancy and hormones are able to induce UGT1A1 enzyme activity. (40) Raltegravir has been most frequently evaluated from all HIV-integrase inhibitors in pregnant women.

2.5 Summary of INSTI PK studies during pregnancy

In table 1, a summary of all studies describing pharmacokinetics of HIV-integrase inhibitors in pregnant women is presented.

In figure 1, a forest plot is presenting all Geometric Mean (GM) ratios (90% CI) for the exposure to different HIV-integrase inhibitors measured in the second or third trimester divided by postpartum F

3. Influence of hormones on drug metabolism in pregnancy

The influences of hormones, such as estrogens, progesterone, cortisol and prolactin on the pharmacokinetics of HIV-integrase inhibitors is presented in table 2. There is accumulating evidence that hormones can modulate activity and expression of particular enzymes involved in drug metabolism of drugs such as HIV-integrase inhibitors during pregnancy. In summary, increased levels of estrogens, growth hormones and corticosteroids in pregnancy are mainly responsible for increased oral clearance of elvitegravir by activation of CYP3A4. Increased levels of progesterone and prolactin during pregnancy and subsequently upregulation of UGT1A1 expression is the most important reason for increased oral clearance and lower exposure to dolutegravir and raltegravir. (36)

4. Discussion and conclusion

This review summarized mechanisms, clinical implications and knowledge gaps on pharmacokinetic changes of HIV-integrase inhibitors during pregnancy. Pregnancy related processes have a large impact on pharmacokinetics of HIV-integrase inhibitors due to a high variety of mechanisms which are discussed in this review. The most distinguishing pharmacokinetic parameter of these HIV-inhibiting drugs is their difference in hepatic metabolism. Dolutegravir and raltegravir are mainly metabolized by UGT1A1, while elvitegravir is primarily metabolized by CYP3A4. Because of increased hormone levels during pregnancy, both of these iso-enzymes are induced resulting in lowered HIV-integrase inhibitor concentrations. Given the most experience in clinical use of raltegravir in pregnancy, this HIV-integrase inhibitor is currently primarily chosen as part of the cART regimen in HIV-infected pregnant women. Evidence and pharmacokinetic data about clinical use of dolutegravir and elvitegravir in this population increases thereby enabling addition of these HIV-integrase inhibitors to the ARV regimen in the future. Each individual HIV-integrase inhibitor possesses unique differences in pharmacokinetics and pharmacodynamics enabling physicians to prescribe patient-tailored drugs to HIV-infected pregnant women. Therefore, more knowledge on pharmacokinetics and safety of each HIV-integrase inhibitor in pregnant women will contribute to implementation of these drugs in perinatal HIV-guidelines.

Increased hormone levels affect pharmacokinetics of HIV-integrase inhibitors during pregnancy. While cortisol levels are three times increased, estrone levels are 300 times increased during pregnancy compared to non-pregnant women. Because many hormones are able to upregulate expression of UGT1A1 or CYP3A4 iso-enzymes, this results in decreased maternal plasma concentrations of HIV-integrase inhibitors in pregnant women and thus suboptimal antiretroviral therapy. Because hormones affect drug transporters and metabolizing enzymes differently, increased hormone levels not necessarily result in altered pharmacokinetics of HIV-integrase inhibitors. In example, progesterone is able to up-regulate expression of UGT1A1, thereby affecting dolutegravir and raltegravir plasma concentrations, but not elvitegravir. (36) To account for these altered pharmacokinetics on a patient level, all hormone levels need to be measured during different trimesters of pregnancy and post-partum in HIV-infected women. This will be a very useful tool for optimal dosing of HIV-integrase inhibitors in pregnant women and enables clinicians to choose the most appropriate drug based on hormonal and pharmacokinetic changes. New studies need to examine prospectively in large study samples whether pregnancy influences elimination half life of HIV-integrase inhibitors. For this purpose, excretion of HIV-integrase inhibitors needs to be measured in faeces and urine. Elimination half-life is hard to estimate based on steady-state conditions of drugs.

Interactions of HIV-integrase inhibitors with mineral supplements are also important to account for. Because all available HIV-integrase inhibitors are 2-metal binders, co-administration of metal cations, such as calcium or iron tablets, may affect bioavailability of HIV-integrase inhibitors. Therefore, dolutegravir needs to be administered two hours before or six hours after calcium or iron administration in fasted state, or it needs to be co-administered with a high-fat meal. To account for these administration times enables physicians and patients to construct adequate anti-HIV dosing regimens and a successful HIV-treatment. (41)

Currently, “second-generation” HIV-integrase inhibitors are being developed aimed at retaining efficacy against patients with resistance for raltegravir or elvitegravir. From the “first-generation” HIV-integrase inhibitors, exclusively dolutegravir is approved for treatment-naïve and –experienced patients. (42) From the “second-generation” group, both bictegravir and cabotegravir are promising and are examined in various clinical trials. (43-46) Cabotegravir shares most of the structure of dolutegravir. (47) This may result in a lower chance to develop resistance among HIV-infected pregnant women. Bictegravir is the newest “second-generation” anti-HIV drug, so very few information is available on its resistance pattern in vivo. A phase II study which was recently performed showed that HIV-infected individuals did not have resistance-associated changes in integrase enzyme after 48 weeks of use. (44) These promising results contribute to lower resistance rates in HIV-infected patients while the amount of novel potent anti-HIV drugs physicians can choose from increases.

In conclusion, new studies need to examine prospectively in large study samples whether pregnancy influences elimination half life of HIV-integrase inhibitors. This increases the generalizability of the study outcomes and increases our knowledge about altered pharmacokinetics of HIV-integrase inhibitors in HIV-infected pregnant women.

5. Conclusion

MESH Terms:

• (“integrase inhibitors”[MeSH Terms] OR (“integrase”[All Fields] AND “inhibitors”[All Fields]) OR “integrase inhibitors”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) AND (“pregnancy”[MeSH Terms] OR “pregnancy”[All Fields]) – 45 hits

• (“integrase inhibitors”[MeSH Terms] OR (“integrase”[All Fields] AND “inhibitors”[All Fields]) OR “integrase inhibitors”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) AND (“gravidity”[MeSH Terms] OR “gravidity”[All Fields] OR “pregnant”[All Fields]) – 15 hits

• (“dolutegravir”[Supplementary Concept] OR “dolutegravir”[All Fields]) AND (“gravidity”[MeSH Terms] OR “gravidity”[All Fields] OR “pregnant”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) – 11 hits

• (“JTK 303″[Supplementary Concept] OR “JTK 303″[All Fields] OR “elvitegravir”[All Fields]) AND (“gravidity”[MeSH Terms] OR “gravidity”[All Fields] OR “pregnant”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) – 2 hits

• (“raltegravir potassium”[MeSH Terms] OR (“raltegravir”[All Fields] AND “potassium”[All Fields]) OR “raltegravir potassium”[All Fields] OR “raltegravir”[All Fields]) AND (“gravidity”[MeSH Terms] OR “gravidity”[All Fields] OR “pregnant”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) – 25 hits

• (“dolutegravir”[Supplementary Concept] OR “dolutegravir”[All Fields]) AND (“pregnancy”[MeSH Terms] OR “pregnancy”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) – 16 hits

• (“JTK 303″[Supplementary Concept] OR “JTK 303″[All Fields] OR “elvitegravir”[All Fields]) AND (“pregnancy”[MeSH Terms] OR “pregnancy”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) – 12 hits

• (“raltegravir potassium”[MeSH Terms] OR (“raltegravir”[All Fields] AND “potassium”[All Fields]) OR “raltegravir potassium”[All Fields] OR “raltegravir”[All Fields]) AND (“pregnancy”[MeSH Terms] OR “pregnancy”[All Fields]) AND (“hiv”[MeSH Terms] OR “hiv”[All Fields]) – 55 hits

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Table 1, Overview of studies and case reports describing pharmacokinetics of HIV-integrase inhibitors in pregnant women and possible mechanisms for altered pharmacokinetics

INSTI + reference

Study design

Cord/

maternal blood ratio

Difference PK parameters during pregnancy

Possible mechanism

GM AUC0-24h (h*mg/L)

1 -> AUC0-12h

2 -> median

Cmin (mg/L)

2 -> median

Cmax

2 -> median

T1/2

(h)

2-> median

Measured during pregnancy or delivery

Dolutegravir

50 mg (33)

Prospective cohort study

1.06

Yes

Lower concentrations due to increased expression of OATP2B1 transporters. (48)

Delivery

Dolutegravir 50 mg (25)

Case report

1.25

Yes, >50% reduction of AUC0-24h during gestation

48

0.9

4.0

12

3rd trimester

106

3.3

5.4

22

Postpartum

Dolutegravir 50 mg (22)

Non-randomized open label phase IV study

– Decreased AUC, Cmin and Cmax

– Decreased T1/2

– Increased CL/F

Induction of UGT1A1 activity, induced by increased progesterone levels and induced CYP3A4 resulting in lowered DTG concentrations.

58.42

0.862

4.592

10.52

2nd trimester

48.72

0.862

3.922

11.22

3rd trimester

71.12

1.702

5.102

12.32

Postpartum

Elvitegravir 150 mg (26)

Case report

1.0

Similar AUC0-24h values during gestation and postpartum

Decreased cobicistat concentrations in pregnancy -> lower elvitegravir concentrations due to decreased boosting and lower Cmax values.

15.0

0.06

1.20

4.1

3rd trimester

14.0

0.15

1.10

6.7

Postpartum

Elvitegravir 150 mg (33)

Prospective cohort study

0.71

Delivery

Elvitegravir 150 mg (34)

Open label, prospective phase IV study

Decreased AUC, Cmax and T1/2 and increased CL/F

Physiological changes during pregnancy, such as increased body volume, result in lower exposure to elvitegravir.

15.72

1.4632

3.12

2nd trimester

14.52

1.4552

3.52

3rd trimester

26.82

1.8762

8.92

Postpartum

Elvitegravir 150 mg(13)

Case report

0.64 (total)

0.9 (free)

– Decreased total Cmin and Cmax, AUC0-24h and T1/2

– Increased total CL/F, AUC0-24h and Cmax of unbound fraction

14.3

0.018

1.27

2.6

3rd trimester

15.4

0.061

1.35

3.7

Postpartum

Raltegravir 400 mg twice daily (23)

Open-label, multicenter, phase 4 study

1.21

– Decreased AUC0-12h and C12h (high interindividual variability)

– Decreased C12h

– Similar elimination half-life

Increased volume of distribution and increased UGT1A1 activity during pregnancy leading to lower AUC & C12h.

5.00 1

1.43

2.55

3rd trimester

7.111

1.76

2.53

Postpartum

Raltegravir 400 mg twice daily (39)

Multicenter, prospective study

1.50

– Decreased AUC0-12h (~50%)

– Decreased C12h (high interindividual variability)

Increased UGT1A1 activity resulting in lower exposure to raltegravir and raltegravir concentrations.

6.62

0.0472

2.252

2.92

2nd trimester

5.42

0.0572

1.772

3.72

3rd trimester

11.62

0.04742

3.0352

3.62

Postpartum

Figure 1, Forest plot presenting all Geometric Mean (GM) ratios (90% CI) for the exposure measured in the second or third trimester divided by postpartum

Table 2, Alterations in hormones during prengancy and their influence on pharmacokinetics of HIV-integrase inhibitors in HIV-infected pregnant women

Hormone group

Hormones

Concentration during pregnancy compared to pre-pregnant phase

(Hypothetical) mechanisms

Clinical consequences

Estrogens

Estradiol

100-fold higher plasma concentrations compared to pre-pregnant phase (36)

– Activation of estrogen receptor alpha (ERα) resulting in up-regulation of UGT1A4.

– Upregulation CYP3A4 expression (36, 37)

– Sodium retention followed by water retention (9)

– Induction of expression of MRP3 transporters in kidneys or liver (49)

– Increased oral CL of HIV-integrase inhibitors

– Lower DTG and EVG concentrations. (36, 37)

– Increased body volume, decreased Cmax of hydrophilic drugs (9)

– Decreased concentrations of HIV-integrase inhibitors in circulation.

Estriol

30-fold higher concentrations during pregnancy compared to non-pregnant women (36)

Activation of several CYP enzymes and stimulation of antibody production against innocuous antigens (50)

Increased oral clearance of HIV-integrase inhibitors and increased immunologic protection during pregnancy.

Estrone

300-fold higher concentrations during pregnancy compared to non-pregnant women (36)

Activation of extracellular-regulated kinase (ERK) and constitutive androstande receptor (CAR) resulting in induction of e.g. CYP3A4 (36)

Increased oral clearance of HIV-integrase inhibitors during pregnancy.

Progesterone

Progesterone

100-fold higher plasma concentrations compared to pre-pregnant phase (36)

– Activation of pregnane X receptor (PXR) resulting in up-regulation of UGT1A1 expression. (36)

– Delayed gastric emptying and prolonged small bowel time resulting in altered bioavailability parameters (9)

– Increased oral clearance of HIV-integrase inhibitors during pregnancy.

– Decreased Cmax and increased Tmax

Growth hormones

human placental lactogen (hPL) and placental growth hormone (PGH)

Respectively 30- and 100-fold higher plasma concentrations compared to pre-pregnant phase(36)

Source: Essay UK - https://www.essay.uk.com/essays/science/pharmacokinetics-of-hiv-integrase-inhibitors/


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